EP3735128A1 - Compositions d'inhibition de biofilm destinées à l'amélioration de prise de poids du bétail - Google Patents

Compositions d'inhibition de biofilm destinées à l'amélioration de prise de poids du bétail

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Publication number
EP3735128A1
EP3735128A1 EP19702139.7A EP19702139A EP3735128A1 EP 3735128 A1 EP3735128 A1 EP 3735128A1 EP 19702139 A EP19702139 A EP 19702139A EP 3735128 A1 EP3735128 A1 EP 3735128A1
Authority
EP
European Patent Office
Prior art keywords
acid
compounds
animal
group
biofilm
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19702139.7A
Other languages
German (de)
English (en)
Inventor
Dlawer Ala'aldeen
Jafar Mahdavi
Panos Soultanas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akeso Biomedical Inc
Original Assignee
Akeso Biomedical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/860,989 external-priority patent/US10653658B2/en
Application filed by Akeso Biomedical Inc filed Critical Akeso Biomedical Inc
Publication of EP3735128A1 publication Critical patent/EP3735128A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/10—Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
    • A61L2/16—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using chemical substances
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/14—Paints containing biocides, e.g. fungicides, insecticides or pesticides

Definitions

  • the present invention generally relates to a class of compounds that has a broad range of microbial biofilm inhibiting antimicrobial and other activities, as well as numerous other uses, especially as feed additives.
  • the first criteria relates to the amount of feed intake required to produce a specified amount of weight gain.
  • the second criteria relates to the amount of daily weight gain (frequently referred to as average daily gain, or ADG) on a specified type and/or amount of feed, whether it is forage, grazing and/or grain.
  • ADG average daily gain
  • compositions have been used to enhance feed efficiency and ADG. Some of these, such as growth hormone, can be overused and leave residues in the meat which then impact the consumer. Others are relatively expensive for the amount of gain. Still others require extensive regulatory testing as being pharmaceutical, not merely nutritional supplements.
  • compositions, and methods of use thereof to improve growth performance in livestock and aquaculture.
  • compositions containing the compounds have been developed which are useful as selective biofilm inhibiting compounds, which can also be utilized in formulations administered to animals to increase feed efficiency and weight gain, as well as to decrease infection by and spread of disease organisms.
  • x is an integer value of 1-2
  • y is an integer value of 1-3
  • each ligand present is independently a conjugate base of an a- hydroxy acid selected from citric acid, tartaric acid, lactic acid, glycolic acid, quinic acid, glycolic acid, isoleucic acid, valic acid, malic acid, and mandelic acid; or each ligand is a conjugate base of an amino acid independently selected from the group consisting of glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine; and salts and/or hydrates thereof.
  • an amino acid independently selected from the group consisting of glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isole
  • Exemplary compounds include Ferric lactate (Fe-Lac), Ferric Citrate (Fe-Cit), Ferric Tartrate (Fe-Tart), Ferric Glycinate (Fe-Gly), Ferric EDTA, Ferric Malate, Ferric oxalate, Ferric Quinate (Fe-QA, also referred to herein as FeQ or QPLEX), and ferric complexes with L-tyrosine (Fe-Tyr, also referred to as TYPLEX), L-DOPA (Fe-DOPA), L-phenylalanine (Fe-Phe) and hydrates, salts, or derivatives thereof.
  • the lactate, citrate, glycinate, tartrate, malate, oxalate, and EDTA forms have an advantage of being more water soluble, and therefore may be easier to manufacture and utilize in solution or feeds.
  • the compounds can be administered to an animal or human for selective inhibition of biofilm formation, as a tablet, capsule, oral solution or suspension, or incorporated into feed or feed supplement.
  • the compositions are effective against a wide range of microbial species including S.
  • the compounds represent a new class of biofilm inhibitors compared to most currently in use, and are effective in treatment and prevention of microbial infections.
  • the compounds can also be administered in conjunction with antibiotics to reverse antibiotic resistance of bacteria, and can be used to treat antibiotic resistant bacteria by administering the compounds with antibiotics.
  • the compounds can be applied to a substrate such as a medical device, tubing, processing equipment, or equipment in the food, medical or computer industries where biofilm formation and bacterial contamination are an issue.
  • the compositions may be incorporated into a coating which is sprayed on as a solution or suspension, incorporated into a laminate, film or polymer coating, or dispersed in particulate or aerosols for administration.
  • the compounds may also be incorporated into solutions or suspensions for application as a disinfectant to an infected surface or a surface having a biofilm thereon. These may also be used as disinfectants for agricultural products such as meat.
  • the compounds are used to improve growth performance of animals such as livestock, including poultry, cattle, sheep, swine and goats, and other animals such as fish, shrimp, and other animals in aquaculture, preferably in the form of feed and formula supplements, in place of, or in combination with, existing bacteriostatic or bactericidal or growth enhancing compounds.
  • the compositions may be administered to animals, such as livestock, to increase growth performance.
  • the compositions may also be used to decrease mortality adjusted feed conversion ratios (MFCR). Examples demonstrate efficacy in enhancing weight gain in livestock including poultry (chickens) and swine.
  • Fig. 1 is a bar graph of the average body weight at day 42 for chickens for all chicken treatment groups described in Example 1 , and a comparison to a commercial control labeled“Target”.
  • Treatment group 1 is the negative control labeled“CNC”.
  • the positive control (labeled“CC”) was challenged with dirty litter containing Campylobacter at day 20.
  • Fig. 2 is a bar graph of the mortality adjusted feed conversion rate (MFCR) at day 42 for all chicken treatment groups described in Example 1, and a comparison to a commercial control labeled“Target”.
  • MFCR mortality adjusted feed conversion rate
  • Fig. 3 is a bar graph of the number of Campylobacter colony forming units per gram (cfu/g) of bird droppings at day 42 for treatment groups 1-3 and 6-8 of Example 1.
  • Fig. 4 is a bar graph of the average number of Campylobacter colony forming units per gram (cfu/g) of caeca samples at day 42 for treatment groups 1-3 and 5-8 of Example 1.
  • Fig. 5 is a bar graph showing the biofilm coverage rate of PAOl Pseudomonas aeruginosa on the surface of a glass slide, comparing PAOl Pseudomonas with no Fe-Lac and PAOl Pseudomonas + 50, 100, and 300 mM Fe-Lac treatment, described in Example 2.
  • Fig. 6 is a bar graph showing the biofilm coverage rate of PAOl Pseudomonas aeruginosa on the surface of a glass slide, comparing PAOl Pseudomonas with no Fe-Cit and PAOl Pseudomonas + 100 and 300 mM Fe-Lac treatment, described in Example 3.
  • Fig. 7 is a bar graph showing the biofilm coverage rate of PAOl Pseudomonas aeruginosa on the surface of a glass slide, comparing PAOl Pseudomonas with no Fe-Tart and PAOl Pseudomonas + 100 and 300 pM Fe-Tart treatment, described in Example 4.
  • Fig. 8 is a bar graph showing the biofilm coverage rate of PAOl Pseudomonas aeruginosa on the surface of a glass slide, comparing PAOl Pseudomonas with no Fe-Gly and PAOl Pseudomonas + 100 and 300 mM Fe-Gly treatment, described in Example 5.
  • Fig. 9 is a bar graph showing the biofilm coverage rate of
  • Campylobacter jejuni NCTC11168 strain on the surface of beads comparing the effect of Fe-Tart at 50 mM, 100 mM, and 300 mM, the effect of FeQ
  • Fig. 10 is a bar graph showing the average number of colony forming units perml (cfu/ml) of CF Lung Isolate No.11 from SED Strains versus no, 100 and 300 pg treated with Ferric EDTA, Ferric Malate and Ferric Oxalate.
  • Fig. 11 is a bar graph showing the average number of Campylobacter colony forming units per gram (cfu/g) of caeca samples at day 35 for groups treated with Ferric.lactate, FeQ (Q-PLEX), and a positive control, of Example 9.
  • Fig. 12 is a bar graph showing the average body weight at day 42 for all treatment groups described in Example 9.
  • Fig. 13 is a graph showing the mortality adjusted feed conversion rate (MFCR) at day 42 for all treatment groups described in Example 9.
  • Fig. 14 is a graph showing the number of Campylobacter colony forming units per gram (cfu/g) of caeca at day 42 for all treatment groups described in Example 9.
  • Fig. 15 is a graph showing the number of Salmonella colony forming units per gram (cfu/g) of caeca at day 42 for all treatment groups in Example 9.
  • Fig. 16 is a graph showing the number of E. coli colony forming units per gram (cfu/g) of caeca at day 42 for all treatment groups described in Example 9. DETAILED DESCRIPTION OF THE INVENTION
  • alkyl refers to the radical of saturated aliphatic groups (i.e., an alkane with one hydrogen atom removed), including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, and C3-C30 for branched chains), preferably 20 or fewer, more preferably 15 or fewer, most preferably 10 or fewer.
  • preferred cycloalkyls have 3-10 carbon atoms in their ring structure, and more preferably have 5, 6, or 7 carbons in the ring structure.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
  • carbonyl such as a carboxyl, alkoxycarbonyl, formyl, or an acyl
  • thiocarbonyl such as a thioester, a thi
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), and -CF3, -CN. Cycloalkyls can be substituted in the same manner.
  • heteroalkyl refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkoxyl or “alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • alkoxyl groups include methoxy, ethoxy, propyloxy, tert- butoxy.
  • An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl and ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, and -O-alkynyl.
  • the terms“aroxy” and“aryloxy”, as used interchangeably herein, can be represented by -O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined below.
  • the alkoxy and aroxy groups can be substituted as described above for alkyl.
  • Aryl refers to C5-Cl0-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or
  • aryl includes 5-, 6-, 7-, 8-, 9-, and lO-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine,.
  • aryl heterocycles or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino (or quaternized amino), nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,
  • heteroaromatic moieties -CF3, -CN, and combinations thereof.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e.,“fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls,
  • heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
  • pyrrolidinyl pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5- thiadiazinyl, l,2,3-thiadiazolyl, l,2,4-thiadiazolyl, l,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl.
  • One or more of the rings can be substituted as defined above for“aryl”.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • aralkyloxy can be represented by -O-aralkyl, wherein aralkyl is as defined above.
  • Biofilm refers any group of microorganisms in which cells stick to each other on a surface.
  • “Cleaning formulation”, as used herein, means a composition suitable for application to a surface for removing dirt and oils, for disinfecting, or a combination thereof.
  • Cleaning formulations can be antibacterial, antimicrobial, or both.
  • Cleaning formulations are suitable for use on the human skin, when none of the components of the composition are present at concentrations that cause significant signs of irritation when applied to human skin.
  • “significant signs of irritation” include erythema, redness, and/or swelling at the site of injection or at the site of application, necrosis at the site of application, exfoliative dermatitis at the site of application, and severe pain that prevents daily activity and/or requires medical attention or hospitalization.
  • Cleaning formulations can be suitable for use in the human buccal cavity.
  • Cleaning formulations can be suitable for use with articles that, subsequent to exposure and optionally with residual levels of cleaning composition present on and/or in the article, will then be contacted with the human skin or other part of the human body, such as wherein the article (e.g. a denture) will be contacted with the buccal cavity, or will be contacted with the eye (e.g. a contact lens).
  • Cleaning formulations can be suitable for use with foodstuffs and/or their packaging and may, for example, be suitable for cleaning meat products and/or carcasses used in the production of meat products.
  • Cleaning formulations may be suitable for cleaning equipment used in food production.
  • Cleaning formulations may be suitable for use in cleaning medical devices, including implantable medical devices. Many other types of cleaning formulations may also be provided by the present invention, further examples of which are discussed in further sections of this application.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur, and selenium. Other heteroatoms include silicon and arsenic.
  • “Inhibition” or “inhibiting” of biofilm formation as used herein refers to a decrease of biofilm associated microorganism formation and/or growth.
  • a “lotion” is a low- to medium-viscosity liquid formulation.
  • MFCR Mediality adjusted Feed Conversion Ratio
  • nitro means -NO2; the term “halogen” designates -F, -Cl, -Br, or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.
  • Oil refers to a composition containing at least 95% wt. of a lipophilic substance.
  • lipophilic substances include but are not limited to naturally occurring and synthetic oils, fats, fatty acids, lecithins, triglycerides and combinations thereof.
  • An“ointment” is a semisolid preparation containing an ointment base and optionally one or more active agents.
  • Parental administration means administration by any method other than through the digestive tract or non-invasive topical or regional routes.
  • a human or non-human animal such as a primate, non-human primate, laboratory animal, farm animal, livestock, or a domestic pet.
  • exemplary animals can optionally include chickens, particularly a meat-type chicken such as broiler chicken, or an egg-laying chicken such as a pullet or hen, or a breeder chicken.
  • poultry such as a turkey, geese, quail or ducks
  • livestock such as cattle, sheep, goats or swine, alpaca, banteng, bison, camel, cat, deer, dog, donkey, gayal, guinea pig, horse, llama, mule, rabbit, reindeer, water buffalo, yak
  • animals including zoo animals, captive animals, game animals, fish (include freshwater and saltwater fish, farmed fish, and ornamental fish), other marine and aquatic animals, including shellfish such as, but not limited to, oysters, mussels, clams, shrimps, prawns, lobsters, crayfish, crabs, cuttlefish, octopus, and squid
  • domestic animals such as cats and dogs, rodents (such as mice, rats, guinea pigs, hamsters), and horses, are also included, as well as any other domestic, wild and
  • “Pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals (such as one or more of the animal “patients” or“subjects” as discussed above) without excessive toxicity, irritation, allergic response, or other problems or complications
  • “Pharmaceutically acceptable salt”, as used herein, refers to derivatives of the compounds defined herein, wherein the parent compound is modified by making acid or base salts thereof.
  • “Therapeutically effective” or“effective amount” as used herein means that the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a condition, bacterial colonization, disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination.
  • therapeutically effective amount “therapeutic amount” and
  • “pharmaceutically effective amount” are synonymous. One of skill in the art can readily determine the proper therapeutic amount.
  • substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl
  • Treatment refers to an intervention performed with the intention of altering or inhibiting the pathology of a disorder.
  • Iron complexes preferably with a molecular weight of the complex less than 1,000 g/mol, are useful for.:
  • Preferred compound include compounds represented by Formula I below, particularly, ferric lactate (also referred to herein as Fe-Lac), ferric citrate (also referred to herein as Fe-Cit), ferric tartrate (also referred to herein as Fe-Tart) and ferric glycinate.
  • ferric lactate also referred to herein as Fe-Lac
  • ferric citrate also referred to herein as Fe-Cit
  • ferric tartrate also referred to herein as Fe-Tart
  • Others include ferric EDTA, ferric malate, and ferric oxalate.
  • a method of enhancing the growth of an animal comprising causing the animal to ingest and/or absorb an effective amount of one or more iron compounds described herein.
  • one or more of the compounds will be presented directly to the animal for ingestion and/or absorption.
  • the animal may be caused to ingest or absorb one or more of the compounds by providing the animal simultaneously, separately or sequentially with components which cause the animal to form an effective amount of the one or more compounds, in situ.
  • the animal could be provided with a source of ferrous sulfate and simultaneously, separately or sequentially with a source of quinic acid or salt thereof (or other oc-hydroxyacid), or could be provided with a source of ferrous sulfate and simultaneously, separately or sequentially with a source of a natural or synthetic amino acid, such as L-tyrosine, L-DOPA or L- phenylalanine.
  • the one or more compounds are a complex of an amino acid with Fe III and a complex of an oc-hydroxyacid with Fe III, or salts and/or hydrates thereof.
  • one or more compounds may be selected from any one or more of the group consisting of a complex of quinic acid with Fe III, a complex of L-tyrosine with Fe III, a complex of L-DOPA with Fe III, and a complex of L-phenylalanine with Fe III, ferric lactate (also referred to herein as Fe-Lac), ferric citrate (also referred to herein as Fe-Cit), ferric tartarate (also referred to herein as Fe-Tart) and ferric glycinate (also referred to herein as Fe-Gly).
  • the one or more compounds is not a complex of quinic acid with Fe III.
  • the animal may be caused to ingest or absorb the one or more of the compounds, by providing the one or more compounds (or component parts thereof to form the compound(s) in situ ) by dietary means, such as in or mixed with an animal feed, as a dietary supplement, and/or in a drinking water.
  • dietary means such as in or mixed with an animal feed, as a dietary supplement, and/or in a drinking water.
  • a further option in the case of marine, aquatic, amphibious or other animals that live partially or fully in water, is to add the one or more compounds (or component parts thereof to form the compound(s) in situ ) into the water, such as by treatment of ponds containing farmed fish or crustaceans such as shrimp and crawfish. It should be noted that, dependent on the solubility of the one or more compounds used, it may be beneficial to introduce a co-solvent to solubilize to aid dissolution in water at an effective concentration.
  • Exemplary animal feed include feed for a chicken (including a broiler chicken and an egg laying chicken).
  • the method includes the steps of incorporating one or more of the compounds into the animal feed product or animal feed supplement product during the preparation of the feed or supplement.
  • An animal feed for use in the methods described herein may include, one or more compounds of the compounds in an amount of 0.001 to 20 g of the one or more compounds per kg of feed, such as 0.002 to 15 g/kg, or at a level of, up to, or at least, about 0.002 g/kg, 0.005 g/kg, 0.01 g/kg, 0.02 g/kg, 0.03 g/kg, 0.04 g/kg, 0.05 g/kg, 0.1 g/kg, 0.
  • An animal drinking water supply of, or for use in, the first aspect may comprise, or be supplemented with, one or more compounds in an amount of 0.001 to 20 g of the one or more compounds per L of water, such as 0.002 to 15 g/L, or at a level of, up to, or at least, about 0.002 g/L, 0.005 g/L, 0.01 g/L, 0.02 g/L,
  • the same concentrations can apply to water in which aquatic or other animals live
  • the one or more compounds may be incorporated into the product at any stage during the production process including before one or more heating steps, such a one or more heating steps that include exposing a composition including the one or more compounds to a temperature of greater than 50°C, greater than 60 °C, greater than 70°C, greater than 80°C, greater than 90°C or greater than 100 °C, and preferably wherein the temperature exposure is in a range selected from 50-200 °C, 60-150 °C, 70-100 °C.
  • a temperature range for a heating step may be in the range of 70-90 °C, such as 75-88°C, 80-87 °C, 81-86 °C, or 82-85 °C.
  • a suitable method for the production of an animal feed such as a feed for a chicken (including a broiler chicken) may include the steps of:
  • cooling the heated mixture Preferably the cooling is conducted at a rate and under conditions effective to avoid the formation of condensation, since condensation can result in the growth of pathogens including Salmonella.
  • Heat sensitive additives can include enzymes, which may (for example) be selected from the group consisting of phytase, xylase, beta-lactamase.
  • the method comprising the step of incorporating one or more of the compounds into the animal feed product at any one or more stages of the production, including during step (a), between steps (a) and (b), during step (b), between steps (b) and (c), during step (c), between steps (c) and (d), during step (d), between steps (d) and (e), during step (e), between steps (e) and (f), during step (f), or after step (f).
  • the one or more compounds may be included in an animal feed, or in an animal feed supplement or premix, for the feed of commercial birds such as chickens, turkeys, pheasants, and ducks.
  • the one or more compounds may be included in, or used to supplement, a poultry feeds, which can be a "complete" feed.
  • a complete feed is designed to contain all the protein, energy, vitamins, minerals, and other nutrients necessary for proper growth, egg production (if the bird is an egg layer), and health of the birds..
  • Chickens used in optimized commercial broiler production are typically fed different diets depending upon their age. For example, chickens for broiler production may be raised using three diets. These diets are typically called a“starter”,“grower” and“finisher”.“Pre-starter” diets are also possible. According, the compounds disclosed herein may be included in a starter diet only, a grower diet only, a finisher diet only, a combination of any two or a combination of all three.
  • The“starter”,“grower” and“finisher” are typically distinguished by crude protein content, which is often provided by ingredients such as soybean meal (SBM).
  • a starter diet for a broiler chicken may optionally contain crude protein contents of around 22-25 % by weight, such as 22%, 23%, 24% or 25%, with 23 or 25% being preferred.
  • a grower diet for a broiler chicken may optionally contain crude protein contents of around 21-23 % by weight, such as 21%, 22% or 23%, with 22% being preferred.
  • a finisher diet for a broiler chicken may optionally contain crude protein contents of around 19-23 % by weight, such as 19%, 20%, 21%, 22% or 23%, with 19%, 20%, or 21% being preferred.
  • the“starter”,“grower” and“finisher” may be distinguished by metabolizable energy (ME) content, which is typically lowest for the starter diet and highest for the finisher diet, with the grower diet having a level between the two.
  • ME metabolizable energy
  • a starter diet for a broiler chicken may have an ME of about 3000 or 3025 kcal/kg ( ⁇ 50, 40,
  • a grower diet for a broiler chicken may have an ME of about 3100 or 3150 kcal/kg ( ⁇ 50, 40,
  • a grower diet for a broiler chicken may have an ME of about 3200 kcal/kg ( ⁇ 50, 40, 30, 20, 10, 5 or less kcal/kg).
  • An animal feed or animal feed supplement fortified as described herein may either be a vegetarian or non- vegetarian product.
  • a vegetarian product contains no meat or fish products.
  • a non-vegetarian diet may contain either, or both, fish product (such as fish meal) or meat product (such as meat derivatives, bone meal, etc.).
  • Similar feed compositions can be made for feeding swine, other types of poultry (ducks, turkeys, pigeons), rabbits, as well as other types of livestock such as sheep, goats, and cattle.
  • Feed compositions are well known for other species of animals, including ruminants such as cattle, sheep and goats, swine, horses, fish and crustaceans (shrimp, crawfish, etc.). Many of these are specific for the age of the animal, such as while still nursing, at weaning, at time of maximum weight gain, during reproduction, and for maintenance. An appropriate amount of compound can be added for purposes such as maximizing weight gain or maintaining or restoring gastrointestinal balance (especially during times of stress such as following antibiotic treatment and at weaning),.
  • Methods for the production of biofilm inhibitor-fortified animal drinking water are also provided.
  • the methods include the addition of one or more of the compounds into an animal drinking water supply.
  • Suitable concentrations of the one or more compounds in a drinking water supply are typically in a concentration effective to produce the effect of enhanced growth in an animal when compared to growth of the animal on drinking water not containing the compounds.
  • a determination of a suitable concentration may take into account the amount of drinking water consumed by the animal.
  • a broiler chicken in the UK typically consumes a daily amount of drinking water dependent on its age that can be calculated by reference to the age of the chicken in days multiplied of approximately 4-10 mL, such as 5-9 ml, 6-8mL, for example about 7.14 mL.
  • a 42 day old broiler chicken may have a daily water consumption of 168 mL to 420 mL per day, more typically around 300 mL per day ⁇ 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, or 1%.
  • Broiler chicken reared at different temperatures may consume more (e.g. in southern USA, where temperatures in the summer will be high and water consumption could be higher, particularly in sheds where temperature is not controlled), or less water.
  • the animal may ingest or absorb an effective amount of one or more of the compounds on a regular and repeated basis. For example, the animal may ingest or absorb an effective amount of one or more compounds weekly, every other day, every day, or more than once every day during the performance of the method or use.
  • the one or more compounds are included in the an animal feed, an animal feed supplement, and/or in drinking water and the animal ingests the one or more compounds when they eat and/or drink, and optionally every time they eat and/or drink.
  • This ingestion or absorption an effective amount of one or more compounds may continue through a period of time of the animal’s growth that may correspond to a period of time that is, is up to, or is at least, 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or substantially 100% of the life of the animal from birth to death.
  • the ingestion or absorption an effective amount of one or more compounds may start on the day of the animal’s birth, or at the age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 days, or more.
  • the animal may continue to do so on a regular and repeated basis for a period of time that can be, or be up to, or at least, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 days, or more.
  • the one or more compounds are preferably ingested on a repeated and regular basis in a starter diet, in a grower diet and/or in a finisher diet, as described herein.
  • An animal drinking water supply of, or for use in, the methods disclosed herein can include or be supplemented with, one or more compounds in an amount of 0.001 to 20 g of the one or more compounds per L of water, such as 0.002 to 15 g/L, or at a level of, up to, or at least, about 0.002 g/L, 0.005 g/L, 0.01 g/L, 0.02 g/L, 0.03 g/L, 0.04 g/L, 0.05 g/L, 0.1 g/L, 0.
  • additives include one or more additives selected from the list consisting of creatine, amino acids (e.g. threonine) and salt, and macro minerals, which include those selected from the group consisting of calcium, phosphorus, magnesium, sodium, potassium and chloride.
  • Added vitamins which include those selected from the group consisting of vitamin A, nicotinic acid, pantothenic acid, pyridoxine (B6) and biotin in maize and wheatbased feed. Additionally there is a basic requirement of broiler chickens for vitamin E at 10-15 mg/kg. The need for extra supplementation with vitamin E will depend on the level and type of fat in the diet, on the level of selenium and on the presence of pro- and anti oxidants. Heat treatment of feeds can result in the destruction of up to 20% of vitamin E. Choline may also be given in a complete feed.
  • Non-nutritive feed additives may also be included. Enzymes are routinely used in poultry feeds to improve digestibility of feed ingredients. In general, feed enzymes are available that act on carbohydrates, plant bound minerals and proteins. Non Starch Polysaccharide (NSP) enzymes are economically beneficial in wheat-based feeds. These enzymes will also allow greater flexibility in the levels of barley to be included in the ration. Phytase enzymes can be used to enhance phytate phosphorus utilization. Protease enzymes can be included to act upon vegetable products. Carbohydrase enzymes can be added, and may provide beneficial responses when used in maize-soya diets. When adding enzymes before heat processing of broiler feeds, there is the potential for a loss in enzyme activity. This may be avoided by spraying enzymes on to the feed at the end of processing.
  • Medicinal and prophylactic drugs may be added.
  • a wide range of medicinal products e.g. coccidiostats and antibiotics, may be administered through the feed.
  • Antibiotic Growth Promoters/Digestion Enhancers can be included and can, for example, provide a mode of action involving modification of the gut microflora, with consequential benefits in nutrient utilization.
  • Prebiotics can be added, and refer to a group of substances which stimulate the growth of beneficial microorganisms, at the expense of harmful, micro-organisms. Oligosaccharides form the largest group of these products at present.
  • Probiotics can be added to introduce live micro-organisms into the digestive tract to assist the establishment of a stable and beneficial microflora.
  • the objective is to provide the gut with positive, non-pathogenic micro- organisms which will then prevent colonization with pathogenic micro-organisms by competitive exclusion.
  • Organic Acids may be added.
  • Organic acid products can be used to reduce bacterial contamination of the feed (e.g. after heat treatment) and can also encourage beneficial microflora to develop in the digestive tract of the bird.
  • Absorbents are used specifically to absorb mycotoxins. They may also have a beneficial effect on general bird health and nutrient absorption. There are a range of products available for use as absorbents, including various clays and charcoal.
  • Antioxidants can provide important protection against nutrient loss in broiler feeds. Some feed ingredients e.g. fish meal and fats, can be protected. Vitamin premixes should be protected by an antioxidant unless optimum storage times and conditions are provided. Additional antioxidants may be added to the final feed where prolonged storage or inadequate storage conditions are unavoidable.
  • Anti-Mold Agents can be added.
  • mold inhibitors may be added to feed ingredients, which have become contaminated, or to finished rations to reduce growth of fungi and production of mycotoxins.
  • pellet binders are hemicellulose, bentonite and guar gum.
  • exemplary“starter”,“grower” and“finisher” diets include those shown in the examples..
  • the starter diet with broiler chicks may be fed for about the first 10- 12 days (typically in the range of the first 7-14 days of life).
  • This starter diet may be followed by the grower diet, which is provided to the broilers for almost 2 weeks (typically from the age of about 11-24 days, although in any case, after the end of the use of the starter diet).
  • the finisher diet may be used for the remainder of the production period (typically from the age of about 24, or 25, days to harvest).
  • Some broiler houses will use more or less diets (for example 4 diets), and vary the timing of diet changes.
  • Broilers are typically harvested between 35 and 42 days, although this time can be longer or shorter.
  • the UK market typically harvests at day 30-35.
  • Non-broiler chickens including free-range chickens, may be harvested at later ages. Any age of harvest may be used, although most typically (e.g. in the context of broiler chickens) after the start of the finisher diet, and optionally (and without limitation) on any of days 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
  • methods for the production of broiler chicken or other animals may be performed on groups that are single sex (i.e. groups of solely female, or solely male animals), and/or may be performed on groups of mixed sex (i.e. mixed male and female) animals.
  • groups that are single sex i.e. groups of solely female, or solely male animals
  • groups of mixed sex i.e. mixed male and female animals.
  • a single sex cockerel group of broiler chickens may be harvested at the age of around 30 days or, in other options, at the age of any one or more of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or more days.
  • an untreated cockerel group may have an average target weight of about 1.95 kg, whereas in the case of the enhanced growth resulting from the methods disclosed herein, it may be appropriate to harvest the cockerels at an earlier stage at the defined target weight, or to harvest at the same age and a higher average weight, or at the same age and target weight with the use of a reduced consumption of animal feed due to greater feed conversion efficiency.
  • a mixed sex group of broiler chickens may be harvested at the age of around 35 days or, in other options, at the age of any one or more of 25, 26, 27, 28, 29, 30, 31, 32, 33,
  • an untreated mixed sex group may have an average target weight of about 2.1-2.2 kg, whereas in the case of the enhanced growth resulting the methods disclosed herein, it may be appropriate to harvest the mixed sex group at an earlier stage at the defined target weight, or to harvest at the same age and a higher average weight, or at the same age and target weight with the use of a reduced consumption of animal feed due to greater feed conversion efficiency.
  • a typical process of rearing an egg-laying chicken can involve the beginning of egg production at around 23 weeks of age, and slaughter at around 60 weeks of age.
  • the egg-laying chicken may be exposed to the one or more compounds prior to beginning egg laying, and/or during egg laying, and/or up to the time of slaughter.
  • Treatment may, for example, last for about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 weeks; the term“about” in that context can include the meaning of ⁇ 4, 3, 2, or 1 weeks of the stated value.
  • egg laying chickens begin to lay eggs at 23 weeks of age
  • the present invention may be used to achieve an effect (compared to an untreated control group that is reared under identical conditions except for the application of the compounds) selected from:
  • Improved quality may, for example, be selected from size, shell quality, air cell, white and yolk.
  • the shell quality is determined from any one or more of size, visual defects, specific gravity, color, breaking strength, percent shell (shell weight x lOO/egg weight), shell thickness, and ultrastructure of the egg.
  • the improved quality may be reflected in a higher proportion of eggs being categorized as US grade A or AA;
  • eggs such as a box or carton of eggs, produced by the animals (especially egg-laying chickens) that have been treated by one of more of the disclosed methods.
  • eggs will typically carry a label indicating their source and/or date of origin.
  • downstream products especially food products, produced from and/or containing eggs or parts thereof produced by the animals (especially egg-laying chickens) that have been treated by one or more of the disclosed methods.
  • the disclosed methods and uses are conducted such that, during the course of the treatment, the animal ingests and/or absorbs a daily mean average total of FeQ (or an equivalent number of moles of any other one or more compounds) of, of up to, or at least, about 1 pg, 10 pg, 100 pg, 500 pg, lmg, 10 mg, 100 mg, 1 g, 2 g, 3 g, 4 g, or 5g.
  • the disclosed methods and uses are conducted such that, during the course of the treatment, the animal ingests and/or absorbs a total of FeQ (or an equivalent number of moles of any other one or more compounds) of, of up to, or at least, about (a) 5 mg, 10 mg, 50 mg, 100 mg, 500 mg, 1 g, 5 g, 10 g, 50 g or 100 g per individual animal and/or (b) 1 mg, 2 mg, 3 mg, 4 mg, 5mg, 10 mg 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 1.1 g, 1.2 g, 13 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2g, 2.lg, 2.2g, 2.3g, 2.4g, 2-5g, 2.6g, 2.7g, 2.8g, 2.9g, 3g, 3.5
  • the method of enhancing the growth may be practiced on multiple animals, which may optionally be reared together and, further optionally wherein all animals reared together may be aged matched to within a month, a week, or less, such as within 6, 5, 4, 3, 2 or 1 days of each other.
  • the method may be practiced on a group of up to, about, or at least, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, lxlO 3 , 2xl0 3 , 3xl0 3 , 4xl0 3 , 5xl0 3 , 6xl0 3 , 7xl0 3 , 8xl0 3 , 9xl0 3 , lxlO 4 , 2xl0 4 , 3xl0 4 , 4xl0 4 , 5xl0 4 , 6xl0 4 , 7xl0 4 , 8xl0 4 , 9xl0 4 , lxlO 5 , 2xl0 5 , 3xl0 5 , 4xl0 5 , 5xl0 5 , 6xl0 4 , 7xl0 4 , 8x
  • the animals treated as disclosed herein may be healthy animals, for example, animals which are not infected with or disadvantageously colonized by bacteria or other microorganisms.
  • the animals may be unhealthy animals, for example, animals which are infected with and/or disadvantageously colonized by bacteria or other
  • an animal that is disadvantageously colonized by bacteria or other microorganisms is an animal which displays a reduced rate of growth, reduced body weight, reduced weight gain, or less efficient feed conversion ratio due to the colonization, compared to a control animal that differs only in that it does not have the colonization.
  • the animal may be animal that have been exposed to the litter (including feacal matter) of one or more other animals of the same or different species.
  • the litter may be from unhealthy animals which, for example, animals which are infected with and/or disadvantageously colonized by bacteria or other microorganisms.
  • the animals treated may be chickens, such as broiler chickens, and they may have been exposed to the litter of other chickens, such as dirty litter as described in the present examples and/or carrying one or more pathogens, such as Actinobacillus, Bordetalla, Campylobacter, Clostridium, Corynebacterium, Escherichia coli, Globicatella, Listeria, Mycobacterium, Salmonella, Staphylococcus, and Streptococcus.
  • pathogens such as Actinobacillus, Bordetalla, Campylobacter, Clostridium, Corynebacterium, Escherichia coli, Globicatella, Listeria, Mycobacterium, Salmonella, Staphylococcus, and Streptococcus.
  • the animals to be treated may be chickens (or other animals) that are infected and/or colonized by one or more of the foregoing pathogens.
  • the disclosed methods and uses may be non-therapeutic, in the sense that the animal to be treated is healthy and/or the method and use comprises the eventual slaughter of the animal.
  • the disclosed methods and uses may include therapeutic benefits to the animals to be treated.
  • the disclosed methods and uses of enhancing the growth of an animal can include enhancing one or more characteristics selected from the group consisting of enhancing body weight or (in the case of a group of animals) average body weight (ABW), feed intake or (in the case of a group of animals) average feed intake (AFD), weight gain or (in the case of a group of animals) average weight gain (AWG), feed conversion ratio (FCR) and/or mortality adjusted feed conversion ratio (MFCR).
  • MFCR over a given period can be calculated as follows:
  • MFCR Total feed intake of period per pen / ((total live weight of pen + total weight of dead birds in pen) - total live weight of pen in previous period)
  • MFCR For example for period 0 to 20 day, MFCR can be calculated as:
  • MFCR o to 20day Total feed intake 0-20 days/ ((Total body weight at day 20 + mortality weight 0-20 days )-Total body weight day o).
  • the enhancement in growth of the animal may be assessed over any convenient period during the animal’s growth. It may, for example, be assessed from birth to a predetermined time point, such as up to about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180 or more days.
  • a predetermined time point such as up to about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180 or more days.
  • the term“about” in this context can mean ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1 days.
  • a predetermined time point such as up to about 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 95%, 96%, 97%, 98%, 99% or 100 % of the life span of the animal. It may, alternatively, not be measured from birth but be measured over a period of the animal’s life lasting up to about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180 or more days. Again, the term “about” in this context can mean ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1 days.
  • enhanced growth may be measured from birth up to the age of slaughter, or may be measured up to an earlier age, such as up to 10, 11, 12, 13, 14, 15, 16, 17 ,18 ,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,
  • the enhanced growth of broiler chickens may not be measured from birth but may be over another period of the broiler chicken’s life lasting, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 ,18 ,19, 20,
  • Enhanced growth can, in some embodiments, refer to an
  • an enhancement in the rate of growth may constitute a reduction in the MFCR of the subject by, by up to, or by at least, about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.20.
  • the term“about” in this context may include the meaning of ⁇
  • the reduction in MFCR may, for example, be measured between days 0 to 20, or days 20 to 42 of the life of the animal(s). Under current economic conditions, it can be calculated that a reduction in MFCR of 0.1 will lead to an approximate saving in feed cost of about 4 US cents per bird over a 42 day growth period and/or about Mother GBP per tonne of animal feed used. It will be appreciated that these are substantial savings in an industry in which costs are typically controlled at a level of about 0.01 US cents per bird.
  • an enhancement in the rate of growth may constitute an increase in the ABW of the subject by, by up to, or by at least, about 10 g, 20 g, 30 g, 40 g, 50 g, 60 g, 70 g, 80 g, 90 g, 100 g, 110 g, 120 g, 130 g, 140 g, 150 g, 160 g, 170 g, 180 g, 190 g, 200 g, 210 g, 220 g, 230 g, 240 g, 250 g or more.
  • the term“about” in this context may include the meaning of ⁇ 5 g, 4 g, 3 g, 2 g or 1 g.
  • the increase in the ABW may, for example, be measured between days 0 to 20, or days 20 to 42 or the life of the animal(s).
  • the increase in the AWG may, for example, be measured between days 0 to 20, or days 20 to 42 of the life of the animal(s), or during a period of time selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 ,18 ,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 36, 37, 38, 39, 40, 41, 42,
  • the foregoing values may be increased proportionately. That is, for example, in the case of an animal that has a normal ABW lO-fold greater than the normal ABW of a broiler chicken, then the enhancement in the rate of growth may constitute an increase in the ABW of the subject by, by up to, or by at least, about 100 g, 200 g, 300 g,
  • 2300 g, 2400 g, 2500 g or more wherein the term“about” in this context may include the meaning of ⁇ 50 g, 40 g, 30 g, 20 g or 10 g.
  • an enhancement in the rate of growth may constitute an increase in the average weight gain (AWG) of the subject by, by up to, or by at least, about 10 g, 20 g, 30 g, 40 g, 50 g, 60 g, 70 g, 80 g, 90 g, 100 g, 110 g, 120 g, 130 g, 140 g, 150 g, 160 g, 170 g, 180 g, 190 g, 200 g, 210 g, 220 g, 230 g, 240 g, 250 g, 260 g, 270 g, 280 g, 290 g, 300 g or more over a period of growth, compared to a control animal or group of animals.
  • AMG average weight gain
  • the term“about” in this context may include the meaning of ⁇ 5 g, 4 g, 3 g, 2 g or 1 g.
  • the increase in the AWG may, for example, be measured between days 0 to 20, or days 20 to 42 of the life of the animal(s), or during a period of time selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 ,18 ,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47 days.
  • animals that normally i.e. when not treated in accordance with the present invention
  • show a higher AWG than the normal AWG of broiler chickens i.e.
  • the foregoing values may be increased proportionately. That is, for example, in the case of an animal that has a normal AWG lO-fold greater than the normal AWG of a broiler chicken over an equivalent period of time, then the enhancement in the rate of growth provided by the present invention may constitute an increase in the AWG of the subject by, by up to, or by at least, about 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900 g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g, 1800 g,
  • 2800 g, 2900 g, 3000 g or more wherein the term“about” in this context may include the meaning of ⁇ 50 g, 40 g, 30 g, 20 g or 10 g.
  • the average age of slaughter of a broiler chicken is 47 days at an average weight of 2.6 kg; at the age of 42 days, the hospitalrge weight may be around 2.5 kg, and in the EU, the average age of slaughter of a broiler chicken 35 days at an average weight of 2.1-2.2 kg.
  • a target body weight of a broiler chicken may be, may be up to, or may be at least, about 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g, 1800 g, 1900 g, 2000 g, 2100 g, 2200 g, 2300 g, 2400 g, 2500 g, 2600 g, 2700 g, 2800 g, 2900 g, 3000 g, 3100 g, 3200 g, 3300 g, 3400 g,
  • the broiler chicken may be slaughtered at, or prior to, the age of 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26 or 25 days, ideally wherein it has reached a target body weight at the time of slaughter.
  • the broiler chicken is reared to a target weight of about 2.6 kg, and the method or use includes the step of slaughtering the animal after having achieved a target body weight 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days earlier than the age of 47 days.
  • broiler chicken is reared to a target weight of about 2.5 kg, and the method or use includes the step of slaughtering the animal after having achieved a target body weight 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days earlier than the age of 42 days.
  • broiler chicken is reared to a target weight of about 2.2 kg, and the method or use includes the step of slaughtering the animal after having achieved a target body weight 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days earlier than the age of 35 days.
  • the animal is reared for the same amount of time as the industry standard, but presents a greater body weight (such as about, at least, or up to, 0.1%. 0.5%. 1%. 2%. 3%, 4%, 5%, 10%, 15%, 20%, 25% or more) than the industry standard at the end of the rearing process.
  • the animal may be slaughtered at a weight of about 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g,
  • 3500 g or more wherein at the time of slaughter body weight is about, at least, or up to, 0.1%. 0.5%. 1%. 2%. 3%, 4%, 5%, 10%, 15%, 20%, 25% or more than the control.
  • the term“about” as it is applied to weight in that context may include ⁇ 50 g, ⁇ 40 g, ⁇ 30 g, ⁇ 20 g or ⁇ 10 g of the stated value.
  • the animal is able to utilize animal feeds with greater efficiency than a control.
  • the disclosed methods and uses include the option of rearing an animal to reach a target body weight using less animal feed than is required for a control to reach the target weight.
  • a target body weight of a broiler chicken may be, may be up to, or may be at least, about 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g, 1800 g, 1900 g, 2000 g, 2100 g, 2200 g, 2300 g, 2400 g, 2500 g, 2600 g, 2700 g, 2800 g, 2900 g, 3000 g, 3100 g, 3200 g, 3300 g, 3400 g, 3500 g or more.
  • the term“about” in that context may include ⁇ 50 g, ⁇ 40 g, ⁇ 30 g, ⁇ 20 g or ⁇ 10 g of the stated value.
  • each chicken in the context of the industry standard for rearing a broiler chicken for 42 days, it is typical to provide each chicken with total of 5.2 kg of feed throughout its life (a mean average of 123.8 g of feed per day of life).
  • one embodiment involves feeding the chicken a total amount of chicken feed that is reduced from 5.2 kg, and/or reduced from a mean average of 123.8 g feed per day, by 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25% or more, during its rearing.
  • the disclosed methods and uses may further comprise the step of rearing the animal to permit enhanced growth.
  • a further embodiment provides a method of preventing or reducing the colonization of the gastrointestinal tract of an animal (such as an animal described above) with Campylobacter and/or other bacterial or
  • microorganisms by causing the animal to ingest and/or absorb an effective amount of one or more compounds.
  • it relates to reduction or prevention of colonization of the gastrointestinal tract of poultry or other animals or humans with Campylobacter
  • a method for disinfection of an animal comprising administering to the animal at least one or more compounds having the structure of Formula I in an effective amount to reduce the number of Campylobacter and/or other bacterial or microorganisms present in the gastrointestinal tract of the animal.
  • a further embodiment also provides a method for disinfection of an animal comprising administering to the animal at least one or more compounds below in an effective amount to prevent the Campylobacter and/or other bacterial or microorganisms from forming a biofilm in the gastrointestinal tract of the animal or to reduce the amount of biofilm formed by Campylobacter and/or other bacterial or microorganisms in the intestinal tract of the animal.
  • a further embodiment also provides a method for preventing or reducing transmission of Campylobacter infection, and/or infection by other bacteria or microorganisms, from one animal to another, for example preventing or reducing spread of Campylobacter and/or infection by other bacteria or microorganism, within a flock or herd of animals, for example preventing spread of Campylobacter infection and/or infection by other bacteria or microorganisms, within a flock of chickens, including broiler chickens; the method comprising administering to the animals, for example the herd or flock of animals, for example the flock of chickens, one or more compounds having the structure of Formula I in an effective amount to prevent the Campylobacter and/or other bacteria or microorganisms, from forming a biofilm in the gastrointestinal tract of the animal or to reduce the amount of biofilm formed by Campylobacter and/or other bacteria or microorganisms, in the intestinal tract of the animal.
  • These methods may allow disinfection, prevention of biofilm formation and reduction of transmission of Campylobacter and/or other bacteria or microorganisms, between animals by preventing or reducing adherence of Campylobacter and/or other bacteria or microorganisms, of the gastrointestinal tract of the animals.
  • This is advantageous because the fewer Campylobacter and/or other bacteria or microorganisms, that are in the gastrointestinal tract of an animal at the time of slaughter, the lower the risk of contamination of meat from the animal with Campylobacter and/or other bacteria or microorganisms.
  • Campylobacter and/or other bacteria or microorganisms will spread from one animal to another, for example within a herd or flock of animals.
  • These methods may also be used to reduce the amount of colonisation of the gastrointestinal tract of any animal with Campylobacter and/or other bacteria or microorganisms. It can be particularly advantageous to provide the one or more compounds having the structure of Formula I to animals that will be slaughtered for human consumption. Poultry includes birds that are used for human consumption such as chickens, geese, turkeys, pheasants, and ducks. It is particularly, advantageous to use the compounds to reduce or prevent colonisation of the gastrointestinal tract of poultry, in particular chickens, and more particularly broiler chickens, egg laying chicken and/or breeder chickens, with Campylobacter and/or other bacteria or
  • microorganisms in the gastrointestinal tracts of animals may be reduced by the methods disclosed herein In one embodiment the number of colony forming units (cfu) of Campylobacter and/or other bacteria or
  • microorganisms in the gastrointestinal tract of an animal treated with the compounds may be reduced by 10%, by 20%, by 30%, by 40%, by 50%, by 60%, by 70%, by 80%, by 90% or by 100%.
  • Campylobacter and/or other bacteria or microorganisms may be substantially eradicated from the gastrointestinal tract of animals treated as disclosed herein.
  • an effective amount of a disclosed compound is enough of the compound to reduce the number of
  • gastrointestinal tract of an animal or on the surface of the bird, such as the neck skin, to a number that is unlikely to cause infection in humans, such as less than 10,000 cfu, 5,000 cfu, 1,000 cfu, 500 cfu, 400 cfu, 300 cfu, 200 cfu, 100 cfu, 90 cfu, 80 cfu, 70 cfu, 60 cfu, 50 cfu or less.
  • the number of cfu of Campylobacter and/or other bacteria or microorganisms that would be ingested by a human if they ate meat from an infected animal may be related to the number of Campylobacter and/or other bacteria or microorganisms in the gastrointestinal tract of the animal at the time of slaughter but also depends on other factors such as the amount of contamination of the meat with the contents of the gastrointestinal tract of the animal at the time of slaughter.
  • An effective amount of the one or more compounds having the structure of Formula I may be an amount that is enough of the one or more compounds to prevent colonisation of the gastrointestinal tract of the animal with Campylobacter and/or other bacteria or
  • the one or more compounds having the structure of Formula I may make Campylobacter and/or other bacteria or
  • microorganisms less virulent and less capable of infecting humans even if the total number of Campylobacter and/or other bacteria or microorganisms in the gastrointestinal tract does not decrease.
  • administering the compound to an animal may affect the metabolism of Campylobacter and/or other bacteria or microorganisms and make them less adaptive to environment (for example, less motile) so that they cannot colonize the gastrointestinal tract and are less likely to be transmitted to other animals or to humans.
  • An effective amount of a one or more compounds provided to an animal should be enough to provide the required degree of reduction of Campylobacter and/or other bacterial or microorganism colonisation. This may depend on the type of compound and/or the size of the animal.
  • the one of more compounds may be provided in an animal feed, animal drink, or other compositions in concentration within the range of about ImM to about 1M, preferably greater than 10 mM, 20mM, 30mM, 40 mM, 50 mM , 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120mM, 130mM, 140 mM, 150 mM , 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 250 mM, 300 mM, 350 mM, 500 mM, 1 mM or more.
  • the concentration of the one or more compounds may be:
  • (c) at least, or about, 345 mM, 350 mM, 360 mM, 370 mM, 380 mM, 390 mM, 400 mM, 450 mM, 0.5 mM, 1 mM, 2 mM or more.
  • the concentration may be within a range selected from the group consisting of from about ImM to about 1 mM, or about 30mM to about 0.5 mM, or about 60 mM to about 0.3 mM.
  • the concentration of the one or more compounds in the composition may be within the range of 0.002 to 15 g/L, or at a level of, up to, or at least, about 0.002 g/L, 0.005 g/L, 0.01 g/L, 0.02 g/L, 0.03 g/L, 0.04 g/L, 0.05 g/L, 0.1 g/L, 0. 2 g/L, 0.3 g/L, 0.4 g/L, 0.5 g/L,
  • the one of more compounds may be provided in an animal feed, animal drink, or other composition in a unit dosage formulation, and/or at a concentration to deliver up to, or at least, about 1 ng, 10 ng, 50 ng, 100 ng, 500 ng, 1 mg, 10 mg, 50 mg, 100 mg, 500 mg, lmg, 10 mg, 100 mg, 500 mg, 1 g, 2 g, 3 g, 4 g, or 5g of the one or more compounds.
  • the disclosed methods and uses may further comprise the step of harvesting a product from the reared animal with enhanced growth.
  • the harvested product may be the body or part of the body of the animal.
  • the harvesting process includes the step of slaughtering the animal and optionally preparing an animal carcass or part thereof as a product, such as a meat product.
  • the harvested body or part of the body of then animal may be a non-food product, a food product, or a precursor of a food product.
  • Carcasses and parts of carcasses may go through a process known as rendering to be made into human and non human foodstuffs, fats, and other material that can be sold to make commercial products such as cosmetics, paint, cleaners, polishes, glue, soap and ink.
  • Such products that may be foodstuffs include but are not limited to blood, bone, including bone char, bone meal, etc., broths and stocks created with animal fat, bone, and/or connective tissue, carmine also known as cochineal (food dye), casein (found in milk and cheese), civet oil (food flavoring additive), gelatin, isinglass (which, may, for example be used in clarification of beer and wine), L-cysteine (which may for example used in the production of biscuits and bread), lard, meat (including fish, poultry, and game), and rennet (commonly used in the production of cheese). Meat and meat products may be of particular interest.
  • carmine also known as cochineal (food dye), casein (found in milk and cheese), civet oil (food flavoring additive), gelatin, isinglass (which, may, for example be used in clarification of beer and wine), L-cysteine (which may for example used in the production of biscuits and bread), lard, meat (including fish, poultry, and
  • the animal is a chicken, for example, a meat-type chicken such as broiler chicken, or an egg-laying chicken such as a pullet or hen, and the product is harvested from the reared animal.
  • the animal is a meat-type chicken, such as broiler chicken, and the harvested product is a carcass or part of the carcass of the chicken.
  • After slaughter to produce the carcass it may or may not be further processed, such as to remove one or more items selected from the group consisting of feathers, offal, neck skin, head, legs, and other items, and may produce a whole dressed carcass ready for sale as a meat product, or ready to send onto further processing.
  • the processed carcass may retain the neck or neck skin, or at least 50%, 60%, 70%, 80%, 90% or more thereof as determined either by length or by weight.
  • the average weight of the neck or neck skin may be in the range of 15-25 g.
  • Further processing may include performing a cut-up operation wherein the carcass is cut into individual parts, and may involve deboning (i.e. where the bones are removed from specific parts) to produce items like breast filets or other boneless products.
  • a process for the slaughter and/or processing of a chicken may include any one or more of the following methodological step: (i) birds arrive at processing plant, typically in plastic crates; (ii) blue light is used to calm the birds; (iii) birds are hung; (iv) birds enter a stun tank; (v) birds are slaughtered using a neck bleed, optionally with a delay stand for bleeding out the birds; (vi) birds skin and/or feathers are heated, for example with water, to loosen pores holding the feathers; (vii) feathers are removed, e.g.
  • alternative methods of stunning the bird are available, and can be substituted for the method indicated in the foregoing method and/or used more generally in accordance the methods and uses disclosed herein.
  • Exemplary alternative methods of stunning the bird include, for example, controlled atmosphere stunning, controlled atmosphere killing, Bi-phasic CO2, and controlled slow decompression.
  • the bird may not be stunned prior to slaughter, e.g. in the case of the production of a meat product in accordance with religious laws, such as Halal, Qurrbani/Udhia, and/or Shechita slaughter laws.
  • the processing of the carcass may be conducted at adequately low refrigeration temperatures, such as around 1, 2, 3, 4 or 5 °C.
  • the carcass or part thereof may be further processed to produce a value added product, and this may include one or more steps required to prepare a consumer-ready product, which may include the addition of any one or more of seasoning, breading, sauces, and marinating, as well as special packaging to meet market demands for convenient products.
  • the harvested product may, for example, be a by-product of the animal, such as milk, eggs, wool, hair, feathers, or litter or other feacal matter and can be collected from the animal without the need to slaughter the animal.
  • Such harvested products may then be further processed and converted into other products.
  • further dairy products can be produced (such as butter, cheese, curd, yoghurt, whey, milk powder, sour cream, dips and other cultured dairy foods, frozen desserts such as ice cream cakes other frozen desserts made with dairy ingredients).
  • further products in particular food products
  • further products containing or produced with the whole or part of the collected eggs can be produced.
  • any and all steps within the entire process of animal rearing, animal harvesting, animal slaughter, carcass processes, animal product production, food production, wrapping, labelling, shipping, stocking and selling may benefit from the application of a surface disinfection or coating as discussed further below.
  • areas for rearing animals may contain one or more disinfected surfaces achieved using the methods, uses and
  • Containers for transporting animals, apparatus used in the slaughter of animals, apparatus used in the processing and/or labelling of an animal carcass, or a part thereof may contain one or more disinfected surfaces achieved using the methods, uses and
  • compositions disclosed herein The animal product, including a carcass, a meat product, or any other animal product produced as disclosed herein may be disinfected using the methods, uses and compositions disclosed herein. Packing, containers and/or wrapping for containing an animal product, including a carcass, a meat product, or any other animal product may be disinfected using the methods, uses and compositions disclosed herein.
  • products produced by, and/or harvested from, animals treated as disclosed herein including any and all products discussed above, and downstream products including or produced therefrom.
  • a meat or meat product produced in accordance with the disclosed methods is provided.
  • it can provide a carcass or part thereof that is of a greater weight than a standard carcass or part thereof, or is from an animal that is younger than a control.
  • carcass or part thereof, or any other product obtained from the animal may have a reduced level of microbial (such as bacterial, including
  • Campylobacter infection or colonization and/or a reduced incidence of biofilms therein, compared to a control.
  • the compounds are particularly useful in treating or preventing infection by antibiotic -resistant microorganisms.
  • the compounds may be administered in order to cause microorganisms to lose their resistance to antibiotics or to increase the sensitivity of microorganism to antimicrobial agents, to potentiate the effect of antibiotics and other antimicrobial agents, and to address antimicrobial and antibiotic resistance.
  • the one or more compounds are selected from the group consisting of a complex of an amino acid with Fe III, and a complex of an oc-hydroxyacid with Fe III, or salts and/or hydrates thereof.
  • the one or more compounds may, or may not, be selected from any one or more of the group consisting of ferric lactate, ferric citrate, ferric tartrate, a complex of quinic acid with Fe III, a complex of L-tyrosine with Fe III), a complex of L-DOPA with Fe III, and a complex of L- phenylalanine with Fe III.
  • the compounds having the structure of Formula I may be used in combination with antimicrobial agents to treat or prevent infection by antibiotic resistant bacteria including
  • Streptococcus pneumoniae Campylobacter, Neisseria gonorrhoeae, Salmonella (including drug-resistant non-typhoidal Salmonella and drug- resistant Salmonella serotype typhi), Methicillin-resistant Staphylococcus aureus (MRSA), Shigella, Vancomycin-resistant Enterococcus (VRE), Vancomycin-resistant Staphylococcus aureus (VRSA), Erythromycin- resistant Group A Streptococcus, Clindamycin-resistant Group B
  • Streptococcus Carbapenem-resistant Enterobacteriaceae (CRE), drug- resistant tuberculosis, Extended spectrum Enterobacteriaceae (ESBL), multidrug-resistant Acinetobacter (including MRAB), Clostridium difficile, Enteropathogenic E. coli (EPEC), Pseudomonas aeruginosa, and
  • Uropathogenic E. coli In another preferred embodiment.
  • the compounds may be used in combination with antimicrobial agents to treat or prevent infection by antibiotic resistant bacteria including S. epidermidis, E. faecalis, E. coli, S. aureus, Enteropathogenic Escherichia coli (EPEC), Uropathogenic Escherichia coli (UPEC), Pseudomonas, Streptococcus anginosus, Salmonella, including Salmonella Enteritidis and Salmonella Typhimurium, Mycoplasma, Eimeria, Enterococci, Brachyspira, and Clostridium perfringen.
  • the compounds and antimicrobial agents may be administered as a pharmaceutical composition or feed additive.
  • Antibiotic-resistant microorganisms may be treated with the one or more compounds and one or more antibiotics or other anti-microbial agents separately, sequentially or simultaneously.
  • the one or more compounds are preferably administered at the same time as the one or more antibiotics or other anti-microbial agents, or preferably such that the compounds and antibiotic(s) are present at the same time. (The compounds and the antibiotics/anti-microbial agents may therefore also be administered sequentially.)
  • the compounds may also be used in combination with antibiotics or other anti-microbial agents to allow smaller doses of antibiotic or other anti microbial agents to be used to treat not only antibiotic-resistant
  • microorganisms and/or other microorganisms resistant to other forms of anti -microbial agent, but also for the treatment of microorganisms that are not resistant to antibiotics or other anti-microbial agents.
  • the compounds could be administered to poultry prophylactically so that a lower dose of antibiotic and/or other anti-microbial agent was required to treat the birds in the event they become infected.
  • compositions for use in a method of treatment or prophylaxis of a microbial infection or colonization in a patient or animal, preferably wherein, in use, the pharmaceutical or veterinary product, medical device or dietary product is administered to the patient or animal separately, simultaneously, or sequentially with the administration of one or more antimicrobials and/or antibiotics.
  • one or more antimicrobials and/or antibiotics for use in a method of treatment or prophylaxis of a microbial infection or colonization in a patient or animal are provided, preferably wherein, in use, the pharmaceutical or veterinary product, medical device or dietary product is administered to the patient or animal separately, simultaneously, or sequentially with the administration of a pharmaceutical or veterinary product, a medical device or a dietary product, wherein the product comprises one or more compounds.
  • the microbial infection or colonization in a patient or animal may, for example, be pathogenic or non-pathogenic microbes.
  • Non-pathogenic microbes can, for example, cause colonization of a host without causing or producing any disease or disorder of the host.
  • the microbial infection or colonization may be prokaryotic or eukaryotic, or a combination of both.
  • prokaryotic microbes include bacteria and archaea.
  • eukaryotic microbes include protists (such as algae, and slime-molds), fungi, multicellular micro-animals and plants including green algaes.
  • Non- limiting examples of bacteria include gram positive bacteria, gram negative bacteria, biofilm-forming bacteria, extracellular bacteria, intracellular bacteria (including facultative and obligate intracellular bacteria), aerobic bacteria, and anaerobic bacteria.
  • Some bacterial genera of interest include Bacillus, Bartonella, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia and Chlamydophila, Clostridium, Corynebacterium, Enterococcus, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria,
  • Mycobacterium Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema,
  • Ureaplasma Vibrio, and Yersinia.
  • Some bacterial species of interest include Bacillus anthracis, Bacillus cereus, Bartonella henselae, Bartonella quintana, Bordetella pertussis, Borrelia burgdorferi, Borrelia garinii, Borrelia afzelii, Borrelia recurrentis, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumonia, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Francis
  • the treatment or prophylaxis as disclosed herein may be directed to one or more microorganism that have resistance or increased tolerance to one or more antimicrobial agents.
  • the one or microorganisms may be, or include, one or more antibiotic-resistant bacteria.
  • Antimicrobial resistance can include the meaning of resistance of a microorganism to an antimicrobial drug that was originally effective for treatment of infections caused by it.
  • Resistant microorganisms are able to withstand attack by antimicrobial drugs, such as antibacterial drugs (e.g. antibiotics), antifungals, antivirals, and antimalarials, so that standard treatments become ineffective and infections persist, increasing the risk of spread to others.
  • antimicrobial drugs such as antibacterial drugs (e.g. antibiotics), antifungals, antivirals, and antimalarials, so that standard treatments become ineffective and infections persist, increasing the risk of spread to others.
  • antimicrobial drugs such as antibacterial drugs (e.g. antibiotics), antifungals, antivirals, and antimalarials
  • the evolution of resistant strains is a natural phenomenon that occurs when microorganisms replicate themselves erroneously or when resistant traits are exchanged between them.
  • the use and misuse of antimicrobial drugs accelerates the emergence of drug-resistant strains. Poor infection
  • the microorganism is an antibiotic -resistant microorganism selected from the group consisting of a gram positive bacterium, a gram negative bacterium, a biofilm- forming bacterium, Streptococcus pneumoniae, Campylobacter, Neisseria gonorrhoeae, Salmonella (including drug-resistant non-typhoidal Salmonella and drug- resistant Salmonella serotype typhi), Methicillin-resistant Staphylococcus aureus (MRSA), Shigella, Vancomycin-resistant Enterococcus (VRE), Vancomycin-resistant Staphylococcus aureus (VRSA), Erythromycin- resistant Group A Streptococcus, Clindamycin-resistant Group B
  • Streptococcus Carbapenem-resistant Enterobacteriaceae (CRE), drug- resistant tuberculosis, Extended spectrum Enterobacteriaceae (ESBL), multidrug-resistant Acinetobacter (including MRAB), Clostridium difficile, Enteropathogenic E. coli (EPEC), Pseudomonas aeruginosa, H. pylori, Streptococcus anginosus and Uropathogenic E. coli (UPEC).
  • CRE Carbapenem-resistant Enterobacteriaceae
  • ESBL Extended spectrum Enterobacteriaceae
  • MRAB multidrug-resistant Acinetobacter
  • EPEC Enteropathogenic E. coli
  • Pseudomonas aeruginosa Pseudomonas aeruginosa
  • H. pylori Streptococcus anginosus
  • Uropathogenic E. coli UPEC
  • the compounds can also be used to increase the sensitivity of non- resistant microorganisms to antimicrobial agents, and thereby provide for a treatment that uses lower dosages of antimicrobial agents, and/or shorter treatment durations with antimicrobial agents, and/or more effective treatment outcomes with antimicrobial agents.
  • the method, or the product for use is for potentiating the antimicrobial (including antibiotic) effect of the separately, simultaneously, or sequentially administered one or more antimicrobial agents (including one or more antibiotics).
  • the amount of the separately, simultaneously, or sequentially administered one or more antimicrobial agents (including one or more antibiotics) may be less than a therapeutically effective or
  • the amount of the separately, simultaneously, or sequentially administered one or more antimicrobial agents (including one or more antibiotics) may be 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more, less than a therapeutically effective or therapeutically optimal dose of the one or more antibiotics when administered to the patient or animal that is not in receipt of the product.
  • the treatment duration of the patient receiving the treatment or prophylaxis of the second embodiment may be 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more, less than the treatment duration required when the patient or animal is not in receipt of the product.
  • the one or more antimicrobial agents is/are an antibiotic.
  • the one or more antibiotics may, for example, be selected from the group consisting of aminoglycosides, ansaycins, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidinones, penicillins, polypeptides, quinolones/fluoroquinolone, sulfonamides, tetracyclines, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, met
  • quinupristin/dalfopristin quinupristin/dalfopristin, thiamphenicol, tigecycline, tinidazole, and trimethoprim; and combinations thereof.
  • the pharmaceutical or veterinary product may include one or more excipients, as a parenteral formulation, including a controlled release formulation, or injectable or implantable formulation.
  • the pharmaceutical or veterinary product may be presented as a enteral formulation, including a controlled release enteral formulation, including extended release dosage forms and delayed release dosage forms.
  • the pharmaceutical or veterinary product may be presented as a topical formulation, including as an emulsion, lotion, cream, ointment, gel, or foam.
  • the product comprising the one or more compounds is a medical device.
  • the device may or may not additionally include the one or more antimicrobial agents (in the embodiment that it does not, then the device and microbial agent are intended to be administered to the subject in separate compositions, either separately, simultaneously or sequentially).
  • Medical devices can include, without limitation, wound dressings, medical implants, tubing and other surface medical devices, such as urinary catheter, stents, mucous extraction catheter, suction catheter, umbilical cannula, contact lenses, intrauterine devices, intravaginal and intraintestinal devices, endotracheal tubes, bronchoscopes, dental prostheses and orthodontic devices, surgical instruments, dental instruments, tubing, dental water lines, dental drain tubes, fabrics, paper, indicator strips (e.g., paper indicator strips or plastic indicator strips), adhesives (e.g., hydrogel adhesives, hot-melt adhesives, or solvent-based adhesives), bandages, tissue dressings or healing devices and occlusive patches, and any other surface devices used in the medical field.
  • urinary catheter stents, mucous extraction catheter, suction catheter, umbilical cannula, contact lenses, intrauterine devices, intravaginal and intraintestinal devices, endotracheal tubes, bronchoscopes, dental prostheses and orthodontic devices, surgical instruments, dental instruments
  • Devices may include electrodes, external prostheses, fixation tapes, compression bandages, and monitors of various types. Medical devices also include any device that may be placed at the insertion or implantation site such as the skin near the insertion or implantation site, and which include at least one surface which is susceptible to colonization by biofilm embedded microorganisms.
  • a composition is integrated into an adhesive, such as tape, thereby providing an adhesive, which can present and/or deliver the one or more compounds on at least one surface of the adhesive.
  • the following devices may comprise, include and/or be coated with the compounds: catheters, including central venous catheters, urinary catheters, dialysis catheters, and indwelling catheters (for example, catheters for hemodialysis and for administration of chemotherapeutic agents), cardiac implants including mechanical heart valves, stents, ventricular assist devices, pacemakers, cardiac rhythm management (CRM) devices, cardiac resynchronization therapy devices (CRTs), and implantable cardioverter defibrillators (ICDs), synthetic vascular grafts, arteriovascular shunts, cerebral spinal fluid shunts, cochlear devices, prosthetic joints, orthopedic implants, internal fixation devices, bone cements, percutaneous sutures, surgical mesh and surgical patches including hernia repair meshes and patches, breast reconstruction meshes and patches, meshes and patches for breast and face lifts, slings, and meshes and patches for pelvic floor reconstruction, tracheal and ventilator tubing, wound dressings, biological implants (including
  • the product comprising the one or more compounds is a dietary product.
  • the dietary product may or may not additionally include one or more antimicrobial agents.
  • Dietary products can include, for example, food stuffs, dietary supplements, drinks, and any other compositions taken orally, which incorporate the one or more.
  • the one or more compounds are selected from the group consisting of a complex of an oc-hydroxyacid with Fe III, or salts and/or hydrates thereof.
  • a further embodiment provides a method for the preparation of a product per se, such as a pharmaceutical or veterinary product, a medical device or a dietary product, that is suitable for use in accordance with the foregoing methods and uses disclosed herein.
  • the method may include the step of mixing, spraying, coating or blending the one or more compounds with the materials forming the formulation or device.
  • compositions 1 and 2 one of which is an iron complex as described herein and the other an antimicrobial, may be temporally separated by up to, about, or at least, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 1 minute, 5 minutes 10 minutes, 20 minutes, 30 minutes 40 minutes 50 minutes 1 hour, 2 hours, 3 hours, 4 hours 5 hours, 6 hours, 7 hours 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours 22 hours 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month or more.
  • Sequential administration includes the meaning of repeated and alternating administrations of
  • Components 1 and 2 in which the administration of either or both components may be repeated any number of times, such as twice, three times, four times, five times, 10 times, 20 times, 30 times or more.
  • Repeated administration of either, or both components, whether administered simultaneously, separately or sequentially, may occur as often as is therapeutically necessary, and can include continuous administration (e.g. by intravenous infusion), of administration up to, about, or at least, every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16 ,17, 18, 19, 20 , 21, 22, 24 or 24 hours, every 1, 2, 3, 4, 5, 6, 7 days, or every 1, 2, 3, 4 or more weeks, throughout the period of treatment.
  • continuous administration e.g. by intravenous infusion
  • the period of treatment is typically selected to achieve a
  • Example of some suitable periods for treatment can include 1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days, about 1, 2, 3, or 4 weeks, or longer.
  • a third aspect of the present disclosure is, based on the surprising finding that the compounds have a broad range of action in treating and dispersing pre-existing biofilms, and inhibiting the development of biofilms, created by a wide range of bacterial and other microbial sources, and that this action is effective in a diverse array of environments.
  • this aspect provides a method of inhibiting biofilm buildup, and/or disrupting a pre-existing biofilm, in or on a subject or article in need thereof, the method comprising administering to the subject or article an effective amount of one or more compounds having the structure of Formula I.
  • the one or more compounds or a salt and/or hydrate thereof, or a functional variant thereof bind to major outer membrane proteins (MOMPs) or FlaA of Campylobacter, a synthetic human histo-blood group antigen, a mimetic of human histo-blood group antigen or a synthetic sugar.
  • MOMPs major outer membrane proteins
  • Particularly preferred compounds include Fe-Lac, Fe-Cit, Fe-Tart, or Fe-malate.
  • Biofilm refers any group of microorganisms in which cells adhere to a surface in a complex structure.
  • Formation of a biofilm begins with the attachment of free-floating microorganisms to a surface. These first colonists adhere to the surface initially through weak, reversible adhesion via van der Waals forces. If the colonists are not immediately separated from the surface, they can anchor themselves more permanently using cell adhesion structures such as pili. Some species are not able to attach to a surface on their own but are sometimes able to anchor themselves to the matrix or directly to earlier colonists. It is during this colonization that the cells are able to communicate via quorum sensing. Once colonization has begun, the biofilm grows through a combination of cell division and recruitment. Polysaccharide matrices typically enclose bacterial biofilms. The final stage of biofilm formation is known as dispersion, and is the stage in which the biofilm is established and may only change in shape and size.
  • a biofilm may comprise, consist essentially of, or consist of, microbial cells growing in a biofilm that are physiologically distinct from planktonic cells of the same organism, which, by contrast, are single-cells.
  • a biofilm may comprise, consist essentially of, or consist of, one species or strain of bacterial cell.
  • a biofilm may comprise, consist essentially of, or consist of, more than one species or strains of bacterial cell, such as up to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000 or more different species or strains of bacterial cell.
  • the bacterial species or strains in biofilms can include bacteria selected from one or more of gram negative, gram positive, aerobic and anaerobic bacteria and/or archaea.
  • compositions and methods for inhibiting, reducing, or removing biofilm forming bacteria and bacterial infections are provided.
  • the biofilm forming bacteria to be inhibited, reduced, removed, or treated may be gram-negative and/or gram-positive bacteria, such as Pseudomonas aeruginosa, Campylobacter jejuni, Helicobacter pylori, Escherichia coli, Enteropathogenic Escherichia coli (EPEC), Uropathogenic Escherichia coli (UPEC), Staphylococcus epidermidis, Staphylococcus aureus, and Enterococcus faecalis.
  • EPEC Enteropathogenic Escherichia coli
  • UPEC Uropathogenic Escherichia coli
  • Staphylococcus epidermidis Staphylococcus aureus
  • Enterococcus faecalis Enterococcus faecalis.
  • biofilm that forms dental plaque.
  • the biofilm in dental plaque typically comprises a variety of microbial organisms, including both aerobic and anaerobic bacteria, and typically includes over 700 different species of bacteria and archaea.
  • Dental plaque biofilms are responsible for many of the diseases common to the oral cavity including dental caries, periodontitis, gingivitis, and the less common peri-implantitis (similar to periodontitis, but with dental implants), however biofilms can be present on healthy teeth as well.
  • the method or use may comprise administering one or more of the disclosed compositions to the mouth of a subject, thereby to achieve the intended effect.
  • dental products may present the buccal cavity or teeth with one or more of the compounds at a concentration within the range of about ImM to about 1M, such as about, or up to, 10 mM, 20mM, 30mM, 40 mM, 50 mM , 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120mM, 130mM, 140 mM, 150 mM , 160 mM, 170 mM, 180 mM, 190 mM, 200 mM,
  • the concentration may be:
  • (c) at least, or about, 345 mM, 350 mM, 360 mM, 370 mM, 380 mM, 390 mM, 400 mM, 450 mM, 0.5 mM, 1 mM, 2 mM or more.
  • the concentration of the one or more compounds may be within a range selected from the group consisting of from about ImM to about 1 mM, or about 30mM to about 0.5 mM, or about 60 mM to about 0.4 mM.
  • the biofilm is biofilm on medical devices, including contact lenses.
  • Biofilms on contact lenses may, for example, comprise, consist essentially of, or consist of one or more bacteria selected from Archromobacter, Delftia, Staphylococcus, Stenotrophomonas, and Streptococci species, and Pseudomonas aeruginosa.
  • the biofilm is biofilms formed on the skin, for example biofilms which comprise, consist essentially of, or consist of Propionibacterium acnes. Accordingly, methods and uses for preventing or inhibiting the formation of, for treating, or for reversing or removing acne and other microbially-induced skin conditions, including recalcitrant and/or anti -biotic resistant conditions, are provided, the method or use comprising the topical administration of a composition as disclosed further herein to the skin of a subject, thereby to achieve the intended effect.
  • biofilms contemplated herein include biofilms that comprise, consist essentially of, or consist of, epsilon proteobacteria class, such as the spirilloid Wolinella spp., Helicobacter spp., and most particularly Campylobacter spp. Many other types of biofilms are contemplated, further examples of which are discussed in further sections of this application.
  • Campylobacter are gram negative, spiral rod shaped bacteria with a single flagellum at one or both poles. They belong to the epsilon
  • proteobacteria class and are closely related to Helicobacter and Wolinella. At least a dozen species of Campylobacter have been implicated in human disease, with C. jejuni and C. coli the most common.
  • Campylobacter jejuni is the major cause of human bacterial gastroenteritis (Pearson, et al., Appl Environ Microbiol., 59:987-996 (1993)).
  • the four major sources of infection are raw meat (particularly poultry), untreated water, raw milk, and pets (Humphrey, et al., J Appl Bacteriol. 61:125-132. (1986) and Skirrow, Int J Food Microbiol., 12:9-16 (1991)). It has also been suggested that, although not universally the case (Humphrey, et al., Public Health Lab Serv Microbiol Digest., 13:86-88.
  • OMPs outer membrane proteins
  • MOMPs major outer membrane proteins
  • Campylobacter spp. possess polar flagella which provide the necessary motility for intestinal colonization.
  • the flagellin gene of Campylobacter has two similar copies: flaA and/Z oB.
  • the length of coding regions for the flaA and/Z oB sequences are both around 1.7 kilobases, and flaA and Z oB sequences locate about 180 bases apart from each other (Meinersmann, et al., Microbiology, 146(9):2283 (2000)).
  • the disclosed compositions bind to major outer membrane proteins (MOMPs) or FlaA of Campylobacter and prevent the bound MOMPs and bound FlaA from binding or associating with their ligands on: other Campylobacter bacteria; other species of bacteria; biofilm or biofilm components; or to surfaces.
  • MOMPs major outer membrane proteins
  • FlaA the compounds inhibit the bacteria from binding to surfaces or each other to produce biofilm.
  • the inhibition of binding can be accomplished by interfering with the binding of natural ligands of MOMPs or FlaA or by physically inhibiting the association of the bacteria expressing MOMPs or FlaA to other organisms or surfaces.
  • the disclosed compositions also bind to the MOMP protein of Campylobacter when MOMP has been mutated to prevent O-glycosylation by mutation of Thr-268 to glycine to form MOMP-T (also referred to as MOMP 12680 ).
  • MOMP-T also referred to as MOMP 12680 .
  • Expression of the MOMP 12680 protein has been found to increase 10-fold compared with wildtype.
  • MOMP 12680 strain with the compositions does not impact planktonic growth, but does partially inhibit biofilm formation demonstrating the compositions bind to the non-glycosylated MOMP with lower affinity.
  • MOMP T268G protein has been found to increase 10- fold compared with wildtype. Regardless of whether MOMP is glycosylated or not, the compositions disclosed herein are still effective against mixed populations of glycosylated and non-glycosylated Campylobacter. In a mixed population of glycosylated and non-glycosylated forms, the wildtype glycosylated form of Campylobacter greatly outcompetes the mutant non- glycosylated form, and over time the non-glycosylated bacteria disappear and the glycosylated bacteria become the only bacteria present.
  • Biofilms are usually found on solid substrates submerged in or exposed to an aqueous solution, although they can form as floating mats on liquid surfaces. Biofilms can form on a myriad of surfaces. For example, biofilms can grow in showers very easily since they provide a moist and warm environment for the biofilm to thrive. Biofilms can form inside water and sewage pipes and cause clogging and corrosion. Biofilms on floors and counters can make sanitation difficult in food preparation areas. Biofilms can form in cooling- or heating- water systems and are known to reduce heat transfer in these systems
  • One method, or use includes administering an effective amount of the one or more compounds of this application to a subject in need thereof, to inhibit biofilm formations, or alternatively, to reduce and/or remove biofilm formation.
  • the one or more compounds may be administered alone, or in combination with an antimicrobial agent, such as an antibiotic.
  • the compounds may be delivered to a chronic wound from a wound dressing.
  • the dressing may also contain one or more antibiotics, and if necessary the wound dressing may be changed frequently.
  • the compounds may also be delivered in a conjugated form (for example, as shown in Figures 15A-C and Figures 16A and B) so that they are immobilized on a surface.
  • the method includes contacting a surface with an effective amount of the compounds, to inhibit biofilm buildup, reduce built up biofilm, and/or remove built up biofilm.
  • Contacting includes, but is not limited to, touching, impregnating, compounding, mixing, integrating, coating, spraying, dipping, flushing, irrigating, and wiping. In certain embodiments, it may be desirable to provide continuous delivery of one or more compounds to the surface or system being treated.
  • the compositions can be used to coat, impregnate, flush, or rinse a surface of tubing or a medical device, especially an insertable medical device.
  • Tubing includes, but is not limited to, disposable, permanent, and indwelling catheters, long term urinary devices, tissue bonding urinary devices, wound drain tubes, ventricular catheters, endotracheal tubes, breathing tubes, feeding tubes, dairy lines, oil and gas pipeline and drinking water lines.
  • an object e.g., dental unit waterline, a dairy line, a food and beverage processing line, etc.
  • a composition may be poured into the tubing and both ends of the tubing clamped such that the composition is retained within the lumen of the tubing.
  • the tubing is then allowed to remain filled with the composition for a period of time sufficient to remove substantially all of the microorganisms from at least one surface of the object, generally, for at least about 1 minute to about 48 hours.
  • tubing may be flushed by pouring a composition into the lumen of the tubing for an amount of time sufficient to prevent substantial growth of all biofilm embedded
  • Such flushing may be required only once, or may be required at regular intervals over the lifetime of use of the tubing.
  • Concentrations of active components in a composition may vary as desired or necessary to decrease the amount of time the composition is in contact with a medical device.
  • the methods allow disinfection, inhibition, or prevention of biofilm formation on the surfaces being treated and reduction of transmission of biofilm forming microorganisms from the surface to another surface.
  • the number of the bacterial colony forming units (cfu) on the surface being treated with the compounds may be reduced by 50%, by 60%, by 70%, by 80%, by 90% or by 100%, or, the buildup of bacterial colony forming units on the treated surface may be reduced by 50%, by 60%, by 70%, by 80%, by 90% or by 100%.
  • compositions and articles including but not limited to pharmaceutical and veterinary compositions, food or feed additive compositions, and dental products including chews may be prepared from the one or more compounds as defined above, optionally formulated and/or used in combination with one or more antibiotics or other anti-microbial agents, and these compositions may further be used for the treatment or prophylaxis of a microbial infection or biofilm formed by bacteria or other
  • microorganisms including one or more of the following: S. epidermidis, E. faecalis, E. coli, S. aureus including Vancomycin-resistant Staphylococcus aureus (VRSA) and Methicillin-resistant Staphylococcus aureus (MRSA), Enteropathogenic Escherichia coli (EPEC), Uropathogenic Escherichia coli (UPEC), Pseudomonas, Streptococcus pneumoniae, Streptococcus anginosus, Neisseria gonorrhoeae, Salmonella (including drug-resistant non- typhoidal, Salmonella including drug-resistant Salmonella serotype typhi, Salmonella Enteritidis, Salmonella Typhimurium, Mycoplasma, Eimeria, Enterococci, Shigella, Vancomycin-resistant Enterococcus (VRE),
  • VRSA Vancomycin-resistant Staphylococcus aureus
  • MRSA Methicillin-
  • the compounds and formulations, derivatives thereof and combinations thereof and be administered topically to a subject in need thereof in an effective amount to prevent or treat a microbial infection, by inhibiting buildup of biofilm or to reduce and/or remove built up biofilm.
  • Any suitable topical formulation can be used, for example as described in Section III.C.3 of this application, below, including emulsions (such as those described in section III.C.3(a)), lotions (such as those described in section III.C.3(b)), creams (such as those as described in section III.C.3(c)), ointments (such as those described in section III.C.3(d)), gels (such as those described in section III.C.3(e)), or foams (such as those described in section III.C.3(f)).
  • emulsions such as those described in section III.C.3(a)
  • lotions such as those described in section III.C.3(b)
  • creams such as those as described in section III.C.3(c)
  • ointments such as those described in section III.C.3(d)
  • gels such as those described in section III.C.3(e)
  • foams such as those described in section III.C.
  • compositions may be used alone or in combination with known antimicrobial agents, such as those described further below in section III.B of this application.
  • compositions are useful for treating topical conditions caused by biofilm buildup by microorganisms including, but not limited to gram negative and gram-positive bacteria, including Staphylococcus (including, but not limited to S. aureus and Staphylococcus epidermidis ), Pseudomonas, E. coll., Streptococcus pyogenes (Reviewed in Nusbaum, et al., Skin Therapy Lett., 17(7): 1-5 (2012)), Propionibacterium acnes and Streptococcus anginosus.
  • microorganisms including, but not limited to gram negative and gram-positive bacteria, including Staphylococcus (including, but not limited to S. aureus and Staphylococcus epidermidis ), Pseudomonas, E. coll., Streptococcus pyogenes (Reviewed in Nusbaum, et al., Skin Therapy Lett., 17(7): 1-5 (2012)), Propionibacter
  • compositions are used as a topical antibacterial medication for skin infections caused by methicillin-resistant Staphylococcus aureus.
  • Methicillin-resistant Staphylococcus aureus is a bacterium that is resistant to many antibiotics.
  • the spectrum of disease caused by MRSA appears to be similar to that of Staphylococcus aureus in the community.
  • Soft tissue infections specifically furuncles (abscessed hair follicles or“boils”), carbuncles (coalesced masses of furuncles), and abscesses, are the most frequently reported clinical manifestations ⁇
  • compositions can also be used to treat MRSA infections of the CNS, which include, but are not limited to Meningitis, Brain abscess, subdural empyema, spinal epidural abscess. Reviewed in Liu, et ak, Clin Infect Dis., 52(3):el8-55 (2011).
  • conditions that can be treated include atopic dermatitis, acne, bullous and non- bullous impetigo, pemphigus foliaceus, miliaria, feruncles (also known as boils) and chronic wounds such as diabetic foot ulcers, venous insufficiency ulcers, and pressure ulcers.
  • an effective concentration of 340 mM is demonstrated in Example 24, although higher or lower concentrations of the one or more compounds according to section III.A below may also be suitable for the treatment of acne and any of the other skin conditions as discussed herein.
  • the treatment of these skin conditions may utilize one or more of the compounds at a concentration within the range of about ImM to about 1M, such as about, or up to, 10 mM, 20mM, 30mM, 40 mM, 50 mM , 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120mM, 130mM, 140 mM, 150 mM , 160 mM, 170 mM, 180 mM, 190 mM, 200 mM,
  • the concentration may be:
  • (c) at least, or about, 345 mM, 350 mM, 360 mM, 370 mM, 380 mM, 390 mM, 400 mM, 450 mM, 0.5 mM, 1 mM, 2 mM or more.
  • the concentration of the one or more compounds may be in within a range selected from the group consisting of from about ImM to about 1 mM, or about 30mM to about 0.5 mM, or about 60 mM to about 0.4 mM.
  • AD Atopic dermatitis
  • aureus colonization and therapy generally fails to improve symptoms in the presence of high S. aureus counts (Akiyama, et ah, J Dermatol Sci., 23(3): 155-6 (2000)). Confocal laser scanning micro has demonstrated the presence of biofilms in skin stripping and biopsy specimens from AD patients (Akiyama, et ah, Br J Dermatol., l48(3):526-32 (2003)). The presence of S. aureus biofilms have been shown in specimens of bullous impetigo and pemphigus foliaceus (Akiyama, et ah, Br J
  • Biofilms have been implicated in miliaria by a clinical study in which only extracellular polymeric substance (EPS) producing S. epidermidis was capable of inducing lesions after inoculation and occlusion (Mowad, et al., J Am Acad Dermatol., 33(5 Pt l):729-33 (1995)). Biopsy specimens revealed sweat glands blocked with EPS material, further supporting a pathogenic role for biofilms in this condition.
  • EPS extracellular polymeric substance
  • Chronic wounds present an optimal environment for microbial proliferation.
  • 60% of chronic wounds were shown to contain biofilms as compared to 6% of acute wounds, indicating a role of biofilms in wound chronicity.
  • Traditional cultures identified Staphylococcus, Pseudomonas, and Enterococcus as the predominant organisms (James, et ak, Wound Repair Regen., l6(l):37- 44 (2008).
  • the compounds may be incorporated into wound irrigation solutions. In another preferred embodiment, the compounds may be incorporated into cosmetic formulations.
  • compositions of the compounds disclosed herein are also useful in oral health for both prophylaxis and treatment of infections.
  • the compounds may be used to treat or prevent infections in dental pulp by Streptococcus anginosus, or prevent attachment of biofilms to tooth surfaces.
  • the compounds may be applied directly to tooth surfaces or applied to dental pulp during a procedure.
  • the compounds may also be incorporated into dental products such as toothpaste, mouthwash, floss, toothpicks, and chewable products (including food products), a mouth shield, a dental instrument, dentures, dental retainers, dental braces including plastic braces (such as Invisalign®), bristles of toothbrushes, dental prostheses and orthodontic devices, chewable non-food items, or foods, as well as applied as coatings directly to dental tissues.
  • the compositions may be used for dental care of both humans and animals, including pets such as dogs and cats as well as livestock and horses.
  • the compounds may be incorporated into chewable foods or toys, such as dog bones and biscuits.
  • a human or animal (especially a dog) chew composition comprising one or more compounds.
  • Exemplary dog and other animal chews which can be modified to include the one or more compounds include those described in US Patent 6,086,940.
  • Further exemplary chews include the Oravet ® dental hygiene chew produced by Merial and the KaNoodles dental chews.
  • Dental chews can be used in dogs and other animals to inhibit the production of biofilms that form plaque, and/or to reduce or treat or prophylactically treat halitosis. Chewing the chews may also help scrub away existing plaque and/or calculus.
  • the chews may be usefully used regularly, such as daily and optionally daily after one or more meals.
  • the compounds may be added to drinking water or other drinkable fluids.
  • Parenteral administration which may include administration to a patient intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically,
  • Parenteral administration can include the use of formulations as described herein which are formulated for controlled release including immediate release, delayed release, extended release, pulsatile release, and combinations thereof, as further herein.
  • injectable/implantable solid or semi-solid implants such as polymeric implants.
  • enteral administration including administration in the form of suitable oral dosage forms such as tablets, capsules, solutions, suspensions, syrups, and lozenges.
  • enteral administration may include administration of controlled release enteral formulations, including oral dosage forms, such as capsules, tablets, solutions, and suspensions, which are formulated for controlled release, including extended and/or delayed release.
  • Methods and uses disclosed herein may be practiced in the hospital and also in other medical and non-medical environments in order to address, inhibit, treat, ameliorate and/or disrupt biofilms. Further examples of microbial infection and colonizations and biofilm formations are discussed further below, including medical uses and methods for the treatment and/or prophylaxis of subjects (including humans and animals) in need thereof.
  • S. epidermidis contributes to biofilms that grow on plastic devices placed within the body (Otto, Nature Reviews Microbiology, 7(8):555-567 (2009)). This occurs most commonly on intravenous catheters and on medical prostheses (Hedin, Scandinavian Journal of Infectious Diseases Supplementum, 90: 1-59 (1993)). Infection can also occur in dialysis patients or anyone with an implanted plastic device that may have been contaminated ⁇ Another disease it causes is endocarditis. This occurs most often in patients with defective heart valves. In some other cases, sepsis can occur in hospital patients.
  • MRSA Methicillin-resistant S. aureus
  • institutions such as hospitals, but are becoming increasingly prevalent in community-acquired infections.
  • Enterococcus faecalis causes many of the antibiotic resistant infections in hospitals, a consequence of its inherent resistance to certain antibiotics and its ability to survive and proliferate in the intestinal tract.
  • Escherichia coli is one of the most frequent causes of many common bacterial infections, including cholecystitis, bacteremia, cholangitis, urinary tract infections other clinical infections such as neonatal meningitis and pneumonia.
  • the compositions can be used to treat (for example, as adjunct therapy) conditions caused by community- and/or hospital-acquired urinary tract infections (UTI's) caused by strains of Escherichia coli (drug resistant or otherwise) in immunocompromised patients.
  • UTI's community- and/or hospital-acquired urinary tract infections
  • the aggressive colonization of stainless steel surfaces by P. aeruginosa for example, apart from being of enormous industrial significance, is also of medical relevance; P. aeruginosa infections are prevalent in bum units where large stainless steel tubs, known as hydrotherapy units, are often used to treat patients with severe bums.
  • Antibiotics are largely ineffective in clearing biofilms, although they may be combined with the compounds in order to potentiate the effect of antibiotics.
  • compositions in accordance with the third aspect of the present disclosure may include hand wash and/or hand spray
  • compositions and may be used accordingly in the treatment of hands and other body surfaces.
  • the one or more compounds for use in the third aspect of the present disclosure can, in accordance with a further embodiment, be used as disinfection (or pesticide) agents (the United States Environmental
  • the one or more compounds may be formulated as a disinfecting formulation or cleaning formulation.
  • a method or use comprising the use of the disinfection agent in high-risk environments such as in hardware from hospitals or healthcare facilities, cosmetic, consumer and industrial applications, to prevent biofilm buildup or reduce biofilm from a surface of interest.
  • the compounds may, for example, be sprayed onto the surface in the form of a foam, solution or gel, or applied to the surface (wipe down) by means of a carrier for example tissue, material or other porous item containing the one or more compounds.
  • the World Health Organization estimates that at any time, more than 1.4 million people worldwide are affected by infections acquired in hospitals. Cleaning, disinfection and sterilization saves lives and improves patient outcomes. Between 5% and 10% of patients admitted to modem hospitals in the developed world acquire one or more healthcare- associated infections.
  • the Centers for Disease Control and Prevention estimate that approximately 1.7 million healthcare-associated infections occur annually in hospitals in the United States, and are associated with nearly 100,000 deaths each year.
  • Healthcare- associated infections are also an important problem in extended care facilities, including nursing homes and rehabilitation units. Transmission of healthcare-associated pathogens most frequently occurs via the hands of healthcare workers, who inadvertently contaminate their hands during various patient care activities. Less frequently, contaminated surfaces in healthcare facilities may contribute to the spread of healthcare-associated pathogens.
  • the varying levels of disinfection used in a healthcare facility may be defined by Spaulding’s Classification (Sehulster, et ah, Guidelines for environmental infection control in health-care facilities. Recommendations from CDC and the Healthcare Infection Control Practices Advisory
  • Spaulding levels, non-critical, semi-critical, and critical, are based on the potential for infectious disease spread via equipment, instruments, and furniture as well as the level of sterility normally required for the body part coming in contact with it. Levels of disinfection that correlate with Spaulding’s classification are low, intermediate, high, and sterilization.
  • the US Centers for Disease Control (CDC) has further delineated disinfection levels for environmental surfaces in its“Guidelines for Environmental Infection Control in Health- Care Facilities”.
  • the third aspect of the present disclosure also provides objects treated for sterilization as described herein, which objects enter sterile tissue or the vascular system and must be sterile because any microbial contamination could transmit disease.
  • This category includes surgical instruments, cardiac and urinary catheters, implants, and ultrasound probes used in sterile body cavities. Semi critical items contact mucous membranes or nonintact skin.
  • This category includes respiratory therapy and anesthesia equipment, some endoscopes, laryngoscope blades, esophageal manometry probes, cystoscopes, anorectal manometry catheters, and diaphragm fitting rings.
  • critical or semi critical instruments include invasive endoscopes such as laparoscopes, and rigid instruments with no operating channel. Arthroscopes and laparoscopes which are inserted into sterile body cavities as well as accessory instrumentation should be sterile. Other examples include gastroscopes, duodenoscopes, sigmoidoscopes, proctoscopes, colonoscopes, bronchoscopes, and laryngoscopes.
  • the compounds may also be used e as food processing aids.
  • solutions of the one or more compounds below could be sprayed on animal carcasses or products (include meat part products) derived therefrom (i.e. poultry, fish, and meat or others, for example, as described above) to prevent or inhibit colonization by bacteria, or inactivate biofilm formation.
  • the compounds could, for example, be applied by dipping chicken (or other animal) carcasses or product derived therefrom in a container of a solution of the compounds, or by spraying an animal carcass with a solution of the compounds.
  • aqueous solutions of Fe-Lac, Fe-Cit, Fe-Tart, Fe-Gly, FeQ, FeTyr, FeDOPA and/or Fe-Phe may be used as food processing aids. After treatment, the compounds may, if desired, be removed by washing.
  • a further embodiment provides an animal carcass (such as a chicken or other poultry, fish or other meat) and/or products (include meat part products) derived therefrom which have been treated, for example by spraying or dipping, and optionally wherein the one or more compounds are subsequently removed fully or partially by washing.
  • an animal carcass such as a chicken or other poultry, fish or other meat
  • products include meat part products derived therefrom which have been treated, for example by spraying or dipping, and optionally wherein the one or more compounds are subsequently removed fully or partially by washing.
  • the compounds can be incorporated into coatings used to coat medical devices, and other articles. Also provided are coated devices or articles, having a coating comprising, consisting essentially of, or consisting of, one or more of the compounds.
  • the compounds can be applied to medical devices and other articles in any number of ways, including, but not limited to, ionic binding to a surface coating, passive adsorption, or dispersion within a polymeric base material making up the surface of the device or coated on the device surfaces (for example by dip coating, spray coating, ultrasonic spray coating, melt processing, application of films, solvent coating, etc.).
  • the one or more compounds are combined with polymers, and coated on medical devices or other articles.
  • Suitable polymers include, but are not limited, to poly(lactides); poly(glycolides); poly(lactide-co-glycolides); poly(lactic acid); poly(glycolic acid); poly(lactic acid-co-glycolic acids); polycaprolactones; poly(orthoesters);
  • polyanhydrides poly(phosphazenes); polyhydroxyalkanoates [including poly-3-hydroxybutyrate, poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHBV), poly-4-hydroxybutyrate, poly-3 -hydroxybutyrate-co-4- hydroxybutyrate] ; synthetically or biologically prepared polyesters
  • polyesters including polyesters with one or more of the following monomeric units: glycolic, lactic; trimethylene carbonate, -dioxanone, or D-caprolactone); poly(lactide-co-caprolactones); polyesters; polycarbonates; tyrosine polycarbonates; polyamides (including synthetic and natural polyamides, polypeptides, and poly(amino acids)); polyesteramides; poly(dioxanones); poly(alkylene alkylates); poly ethers (such as polyethylene glycol, PEG, and polyethylene oxide, PEO); polyvinyl pyrrolidones or PVP; polyurethanes; polyetheresters; polyacetals; polycyanoacrylates;
  • poly(oxyethylene)/poly(oxypropylene) copolymers polyacetals, polyketals; polyphosphates; (phosphorous-containing) polymers; polyphosphoesters; polyalkylene oxalates; polyalkylene succinates; poly(maleic acids); chi tin; chitosan; modified chitosan; collagen; silk; biocompatible polysaccharides; biocompatible copolymers (including block copolymers or random copolymers); hydrophilic or water soluble polymers, such as polyethylene glycol, (PEG) or polyvinyl pyrrolidone (PVP), with blocks of other biocompatible or biodegradable polymers, for example, poly(lactide), poly(lactide-co-glycolide, or polycaprolcatone or combinations thereof, polymers and copolymers of ethylene and propylene, including ultra-high molecular weight polyethylene, ultra-high molecular weight polypropylene, nylon, polyesters such as poly(ethylene terephthal
  • the one or more compounds can be first conjugated with other agents that have an affinity for, or can react with, a surface, and thereby immobilized on a surface.
  • the compounds can be tethered to a linkage that can be photo-activated to bind to a surface, or activated via another mechanism.
  • Examples of devices and articles that can be coated using the compositions include tubing and other surface medical devices, such as urinary catheter, stents, mucous extraction catheter, suction catheter, umbilical cannula, contact lenses, intrauterine devices, intravaginal and intraintestinal devices, endotracheal tubes, bronchoscopes, dental prostheses and orthodontic devices, dentures, teeth, surgical instruments, dental instruments, tubing, dental water lines, dental drain tubes, fabrics, paper, indicator strips (e.g., paper indicator strips or plastic indicator strips), adhesives (e.g., hydrogel adhesives, hot-melt adhesives, or solvent-based adhesives), bandages, tissue dressings or healing devices and occlusive patches, and any other surface devices used in the medical field.
  • surface medical devices such as urinary catheter, stents, mucous extraction catheter, suction catheter, umbilical cannula, contact lenses, intrauterine devices, intravaginal and intraintestinal devices, endotracheal tubes, bronchoscopes, dental prosthese
  • Devices may include electrodes, external prostheses, fixation tapes, compression bandages, and monitors of various types. Medical devices also include any device that may be placed at the insertion or implantation site such as the skin near the insertion or implantation site, and which include at least one surface which is susceptible to colonization by biofilm embedded microorganisms.
  • a composition is integrated into an adhesive, such as tape, thereby providing an adhesive, which may prevent growth or proliferation of biofilm embedded microorganisms on at least one surface of the adhesive.
  • Medical devices include surfaces of equipment in operating rooms, emergency rooms, hospital rooms, clinics, and bathrooms. In a particularly preferred embodiment the following devices may be coated with the compounds: catheters, including central venous catheters, urinary catheters, dialysis catheters, and indwelling catheters (for example, catheters for hemodialysis and for administration of
  • chemotherapeutic agents include mechanical heart valves, stents, ventricular assist devices, pacemakers, cardiac rhythm management (CRM) devices, cardiac resynchronization therapy devices (CRTs), and implantable cardioverter defibrillators (ICDs), synthetic vascular grafts, arteriovascular shunts, cerebral spinal fluid shunts, cochlear devices, prosthetic joints, orthopedic implants, internal fixation devices, bone cements, percutaneous sutures, surgical mesh and surgical patches including hernia repair meshes and patches, breast reconstruction meshes and patches, meshes and patches for breast and face lifts, slings, and meshes and patches for pelvic floor reconstruction, tracheal and ventilator tubing, wound dressings, biological implants (including allografts, xenografts and autografts), penile implants, intrauterine devices, endotracheal tubes, and contact lenses.
  • cardiac implants including mechanical heart valves, stents, ventricular assist devices, pacemakers, cardiac rhythm management (CRM
  • articles that can be coated as disclosed herein include articles for use in rearing animals, articles for use in the process of slaughter and/or processing the carcasses or parts thereof of animals such as animals and articles as disclosed above.
  • Yet further articles that can be as disclosed herein include articles for the preparation and/or containment of food stuffs or drinks, including foodstuffs comprising raw or cooked meats, eggs, dairy products or other food products.
  • the food products may be human and/or animal food products.
  • a method of disinfecting a surface, or protecting a surface against infection, in need thereof comprising contacting the surface with an effective amount of one or more compounds having the structure of having the structure of Formula I, wherein the one or more compounds are coated onto the surface to be disinfected.
  • the one or more compounds may be applied to the surface in the form of a spray, an aerosol, or a foam.
  • the coated surface may, for example, be formed on the surface of an instrument selected from the group consisting of surgical instruments, cardiac and urinary catheters, implants, and ultrasound probes used in sterile body cavities.
  • the coated surface may, for example, be formed on the surface of a device selected from the group consisting of urinary catheter, stents, mucous extraction catheter, suction catheter, umbilical cannula, contact lenses, intrauterine devices, intravaginal and intraintestinal devices, endotracheal tubes, bronchoscopes, dental prostheses and orthodontic devices, surgical instruments, dental instruments, tubing, dental water lines, dental drain tubes, fabrics, paper, indicator strips (e.g., paper indicator strips or plastic indicator strips), adhesives (e.g., hydrogel adhesives, hot-melt adhesives, or solvent- based adhesives), bandages, tissue dressings or healing devices and occlusive patches, catheters, including central venous catheters, urinary catheters, dialysis catheters, and indwelling catheters, cardiac implants, mechanical heart valves, stents, ventricular assist devices, pacemakers, cardiac rhythm management (CRM) devices, cardiac resynchronization therapy devices (CRTs), and implantable cardioverter defibrill
  • the coated surface may, for example, be formed on the surface of an article selected from the group consisting of an industrial pipeline, liquid distribution lines, oil and gas pipelines and cosmetic container.
  • the coated surface may, for example, be formed on the surface of, or be incorporated into, or onto, a household item, such as an item selected from the group consisting of household disinfectants; laundry detergent; cleaning supplies; equipment involved in the leeching process or mining; wound care; toothpaste; mouth wash; dental floss; toothpicks; chewable products (including food products); a mouth shield; a dental instrument; dentures; dental retainers; dental braces including plastic braces (such as Invisalign®); bristles of toothbrushes; dental prostheses and orthodontic devices; chewable non-food items, foods, or toys, such as dog bones and biscuits; a vacuum system; HVAC ((heating, ventilation and air
  • vacuum cleaner bags paint covering; wall coverings; window frames; doors; door frames; cooling towers; humidifiers; vacuum cleaners; filters such as a vacuum filter, a humidifier filter, hot tub filter, or a swimming pool filter; toys; plastic bottles; water jugs; tap and water spout; washing machines; dishwashers; animal water dishes;
  • the coated surface may, for example, be formed on the surface of, or incorporated into, or onto, an article, device or apparatus used in the rearing and/or transport of animals.
  • the device or apparatus used in the rearing and/or transport of animals may be selected from an article, device or apparatus that is for the delivery and/or containment of animal feed and/or animal drinking water.
  • the coated surface may, for example, be formed on the surface of, or incorporated into, or onto, an article, device or apparatus used in the rearing, housing and/or transport of animals
  • the article, device or apparatus used in the rearing, housing and/or transport of animals can include one or more of an article, device or apparatus used in the production, creation, collection, storage, processing and/or packaging of an animal product.
  • an animal product may be a by-product of the animal (e.g. milk, eggs, or wool) or a downstream product thereof.
  • an animal product may be the body or part of the body of the animal, and the harvesting process optionally includes the step of slaughtering the animal and further optionally preparing an animal carcass or part thereof as a product, such as a meat product.
  • a device, article, product, item, formulation, composition or coating may comprise the one or more compounds in the coating in an amount effective to prevent biofilm formation.
  • the device, article, product, item, formulation, composition or coating comprises the one or more compounds in the coating in an amount effective to treat or reduce biofilm formation.
  • compositions contemplated herein also include the direct per se products of the above-defined methods and uses, and downstream product produced therefrom.
  • a compound conjugated to a structure that can anchor to a surface wherein the compound has the structure of having the structure of Formula I. It may be preferred that the compound binds to major outer membrane proteins (MOMPs) or FlaA of Campylobacter, a synthetic human histo-blood group antigen, a mimetic of human histo-blood group antigen or a synthetic sugar.
  • MOMPs major outer membrane proteins
  • FlaA of Campylobacter FlaA of Campylobacter
  • a synthetic human histo-blood group antigen a mimetic of human histo-blood group antigen or a synthetic sugar.
  • composition comprising one or more conjugated compounds as defined above, and an article coated with one or more of the conjugated compounds, or with the composition.
  • the structure of the conjugated compound comprises hydroxyapatite or derivative thereof, and the conjugate is capable of anchoring, or is anchored to, a dental tissue.
  • conjugated forms of the compounds such as those shown in Figures 16A and B wherein the compounds are conjugated to hydroxyapatite may be applied to tooth tissues, such as tooth enamel, dentin and pulp in order to prevent dental caries and infection.
  • the compounds can be applied using photo-reactive chemistry, for example, using conjugated forms of the compounds such as those shown in Figures 15 A and B.
  • compositions can be used in accordance with a further embodiment, disinfect industrial surfaces, by preventing and/or removing biofilm buildup on such surfaces.
  • the formation of the biofilm may be prevented or inhibited, or a preformed biofilm may be removed by a method that comprises applying a composition comprising the one or more compounds having the structure of Formula I, onto a surface in need thereof, for example as a spray, foam, gel, powders; dish or laundry detergents (liquid or solid), surface wax, glass cleaner, etc.
  • Biofilms are continuously produced and often accumulate on numerous industrial surfaces and on biological surfaces. In an industrial setting, the presence of these biofilms causes a decrease in the efficiency of industrial machinery, requires increased maintenance, and presents potential health hazards. For example, the surfaces of water cooling towers become increasingly coated with microbially produced biofilm slime which both constricts water flow and reduces heat exchange capacity. Water cooling tower biofilms may also harbor pathogenic microorganisms such as Legionella pneumophila. Food preparation lines are routinely plagued by biofilm build-up both on the machinery and on the food product where biofilms often include potential pathogens. Biofilm formation comes with associated problems, such as accelerated deterioration of equipment through corrosion from cellular byproducts. There may also be a reduction in the efficacy of heat transfer and impairment of detection devices as the film disrupts transmission.
  • Pseudomonas aeruginosa readily binds to stainless steel or plastic (e.g. polyvinylchloride, polystyrene) surfaces causing major problems in both the medical and food industries, forming biofilm.
  • Biofilms readily form on PVC and glass surfaces under the static condition, especially in the food industry.
  • compositions and coatings disclosed herein can be used to clean, or maintain, pipelines and hoses in industries such as food and beverage industries, paper mills, sewage treatment, drainage, cooling towers and gas and oil industries by contacting a surface with biofilm growth with the composition.
  • Industrial applications include their use in dairy lines, either as a flush or wash for such lines, or incorporated within the lines, for example as a coating; liquid distribution lines in the food and beverage manufacturing or dispensing, for example, use as a coating in feeder lines for high sugar or syrup distribution in the manufacturing of soft drinks; pulp and paper mills (for biofouling); in the manufacturing and containment of cosmetics from production line equipment down to the end consumable, either incorporated within the cosmetic or coated on the jar containing the cosmetic; in water treatment facilities; in the leaching process used in mining; to prevent corrosion caused or accelerated by organisms, in oil and gas pipelines including fracking pipes, in the souring of oil fields, in antifouling coatings (for example on submarines and boats), and in cooling towers.
  • dairy lines either as a flush or wash for such lines, or incorporated within the lines, for example as a coating
  • liquid distribution lines in the food and beverage manufacturing or dispensing for example, use as a coating in feeder lines for high sugar or syrup distribution in the manufacturing of soft drinks
  • Consumer and light commercial uses of the compounds and coatings include their incorporation in general household disinfectants; laundry detergent; cleaning supplies; equipment involved in the leeching process or mining; wound care; a vacuum system; HVAC (heating, ventilation and air conditioning) systems; vacuum cleaner bags; paint covering; wall coverings; window frames; doors; door frames; cooling towers; boat hulls, humidifiers; vacuum cleaners; filters and membranes, such as a vacuum filter, a humidifier filter, hot tub filter, osmosis membranes, or a swimming pool filter; toys; plastic bottles; water jugs; toothpaste, mouthwash, a tap and water spout; incorporation into plastics for a variety of household items including the inside and outside of washing machines and dishwashers; animal water dishes; bathroom tiles and fixtures; sinks; showers; shower heads; toilets; toilets lids; toilet seats; sealants and grout; towels;
  • TUPPERWARE® dishes; cups; utensils such as forks, spoons, knives, and spatulas; bowls; food storage containers; beverage storage containers; cutting boards; dish drying trays; garbage bags; bathtubs including whirlpool and jacuzzi bathtubs; sinks; fish ponds and tanks; swimming pools; swimming pool liners; swimming pool skimmer; pond liners; bird baths; garden hose; water sprinkling lines; planters; and hot tubs.
  • Cosmetics and cosmetic applications as well as containers for cosmetics and applicators for cosmetics that incorporate and/or are coated by, the one or more compounds having the structure of Formula I, are also provided.
  • Cosmetics also known as makeup or make-up
  • care substances used to enhance the appearance or odor of the human body. They are generally mixtures of chemical compounds, some being derived from natural sources (including natural oils) and many being synthetics.
  • a cosmetic may be a substance that is suitable to be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance without affecting the body's structure or functions.
  • soap is traditionally not considered to be a cosmetic, for the purposes of the present description the discussion of cosmetics can also be applied to soaps.
  • Exemplary cosmetics include skin-care creams, lotions, powders, perfumes, lipsticks, fingernail and toe nail polish, eye and facial makeup, towelettes, permanent waves, colored contact lenses, hair colors, hair sprays and gels, deodorants, hand sanitizer, baby products, bath oils, bubble baths, bath salts, butters and many other types of products.
  • a subset of cosmetics is called "make-up,” which refers primarily to coloring products intended to alter the user’s appearance.
  • Cosmetics that are meant to be used on the face and eye area are usually applied with a brush or the fingertips.
  • Cosmetics may comprise a variety of organic compounds and inorganic compounds.
  • Typical organic compounds can include modified natural oils and fats as well as a variety of petrochemically derived agents.
  • Inorganic compounds can include processed minerals such as iron oxides, talc, and zinc oxide. The oxides of zinc and iron may be classified as pigments, i.e. colorants, and may have no solubility in solvents.
  • the application discloses compounds for cosmetics, cosmetic applications, cosmetic containers and/or cosmetic applicators may provide for methods to reduce, avoid, minimise or disrupt biofilms in the cosmetics, containers and/or applicators. Further, insofar as the applicant of the cosmetic to the body of the user achieves the delivery of one or more compounds, then the cosmetics may be used to treat individuals as disclosed herein , particularly in the context of treating, reducing, prevent or disrupting bacterial infections, colonization, or biofilms on the skin, hair, nails, and/or in teeth of the user.
  • a further use of the compounds having the structure of Formula I, and compositions comprising one or more of the compound is to treat any medical condition associated with biofilm formation as a result of microorganisms including, but not limited to gram-negative and gram positive bacteria, including Pseudomonas, H. pylori, E. feacalis,
  • Campylobacter, E. coli, EPEC, UPEC and Staphylococcus Campylobacter, E. coli, EPEC, UPEC and Staphylococcus.
  • MRSA MRSA-resistant bacterial swine swine swine
  • Additional conditions include severe or extensive disease (e.g., involving multiple sites of infection) or rapid progression in presence of associated cellulitis, signs and symptoms of systemic illness, associated comorbidities or immunosuppression, extremes of age, abscess in an area difficult to drain (e.g., face, hand, and genitalia), associated septic phlebitis, and lack of response to incision and drainage alone, purulent cellulitis, hospitalized patients with complicated SSTI (cSSTI; defined as patients with deeper soft-tissue infections, surgical/traumatic wound infection, and infected ulcers and burns), osteomyelitis, device-related osteoarticular infections.
  • cSSTI complex SSTI
  • the compounds having the structure of Formula I may also be used in the treatment of keratitis, colon cancer (where biofilms play a role), and peri-implantitis, a bacterial infection around an implant that results in inflammation of the gums, and can lead to bone loss in the jaw.
  • EHEC enterohaemorrhagic E. coli
  • HUS haemolytic uraemic syndrome
  • Uropathogenic E. coli is the predominant etiologic agent that causes UTIs. Accordingly, the compositions can also be used to inhibit or reduce biofilm involved in lower urinary tract infections (UTIs).
  • UTI UTI’s in human have been traditionally considered to be a self-limiting disease involving bacteria residing in the lumen of bladders. Intracellular bacterial community-like structures also have been identified in the urine sediments of patients with UTIs in a prospective study.
  • the biofilm that is inhibited or disrupted is a bacterial biofilm.
  • the bacteria forming the biofilm may be gram positive, or in an alternative embodiment may be gram negative, or the biofilm may be formed by a mixture of gram positive and gram negative bacteria.
  • the biofilm may be formed by bacteria selected from the group consisting of S. epidermidis, E. faecalis, E. coli, S. aureus, H. pylori, Campylobacter, Enteropathogenic Escherichia coli (EPEC), Uropathogenic Escherichia coli (UPEC), and Pseudomonas or combinations thereof.
  • the biofilm is a biofilm that is formed by bacteria other than bacteria that comprise, consist essentially of, or consist of proteobacteria class, such as any one or more of the spirilloid Wolinella spp., Helicobacter spp., and most particularly Campylobacter spp..
  • the one or more compounds administered to a subject may be a pharmaceutical or veterinary product, and further may include one or more excipients, such as discussed in section III.C of this application, below.
  • the one or more compounds is administered to a subject by one or more routes selected from: parenteral delivery, such as discussed below in section III.C.1 of this application, including a controlled release formulation, such as discussed below in section III.C.1(a) of this application, and injectable or implantable formulation, such as discussed below in section III.C.1(b) of this application; enteral delivery, such as discussed below in section III.C.2 of this application, including a controlled release enteral formulation, such as discussed below in section III.C.2(a) of this application, with further reference to extended release dosage forms and delayed release dosage forms as discussed therein; oral delivery; topical delivery, such as discussed below in section III.C.3 of this application, including as an emulsion, lotion, cream, ointment, gel, or foam as discussed in parts (a), (b), (c), (d) (e) and (f) respectively below in section III.C.3 of this
  • the biofilm may be associated with a bacterial infection selected from the group consisting of impetigo, boils, abscesses, folliculitis, cellulitis, necrotizing fasciitis, pyomyositis, surgical/traumatic wound infection, and infected ulcers and bums), osteomyelitis, device- related osteoarticular infections, impetigo, secondarily infected skin lesions, meningitis, brain abscess, subdural empyema, spinal epidural abscess, arterial damage, gastritis, urinary tract infections, biliary tract infections, pyelonephritis, cystitis, sinus infections, ear infections, otitis media, otitis externa, leprosy, tuberculosis, conjunctivitis, bloodstream infections, benign prostatic hyperplasia, chronic prostatitis, lung infections including chronic lung infections of humans with cystic fibrosis, osteomyelitis, catheter infections, bloodstream infections, benign
  • a further embodiment provides a method of treating a microbial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds having the structure of Formula I.
  • this embodiment also provides for the use of one or more of the compounds for treating a microbial infection in a subject in need thereof.
  • the microbial infection is caused by bacteria, such as gram positive bacteria, or gram negative bacteria.
  • bacteria such as gram positive bacteria, or gram negative bacteria.
  • the infection may be caused by bacteria selected from the group consisting of S. epidermidis, E. faecalis, E. coli, S. aureus, H.
  • the infection is not caused by bacteria that comprise, consist essentially of, or consist of proteobacteria class, such as any one or more of the spirilloid Wolinella spp., Helicobacter spp., and most particularly Campylobacter spp...
  • the one or more compounds may be administered to a subject by parenteral delivery; enteral delivery; oral delivery; topical delivery, such as in the form of an emulsion, lotion, cream, ointment, gel or foam; buccal delivery; sublabial delivery; sublingual delivery; in or on a dental product or dental device, such as a dental product, including but not limited to a toothpaste, a mouthwash, a dental floss, toothpicks, chewable products (including food products), a mouth shield, a dental instrument, dentures, dental retainers, dental braces including plastic braces (such as Invisalign®), bristles of toothbrushes, dental prostheses and orthodontic devices, chewable non-food items, foods, or toys, such as dog bones and biscuits; dermal delivery; or transdermal delivery.
  • parenteral delivery enteral delivery
  • oral delivery topical delivery, such as in the form of an emulsion, lotion, cream, ointment, gel or foam
  • buccal delivery sublabial delivery
  • sublingual delivery
  • the treatment of a microbial infection in a subject in need thereof may be to treat an infection is selected from the group consisting of impetigo, boils, abscesses, folliculitis, cellulitis, necrotizing fasciitis, pyomyositis, surgical/traumatic wound infection, and infected ulcers and bums), osteomyelitis, device-related osteoarticular infections, impetigo, secondarily infected skin lesions, meningitis, brain abscess, subdural empyema, spinal epidural abscess, arterial damage, gastritis, urinary tract infections, biliary tract infections, pyelonephritis, cystitis, sinus infections, ear infections, otitis media, otitis externa, leprosy, tuberculosis, conjunctivitis, bloodstream infections, benign prostatic hyperplasia, chronic prostatitis, lung infections including chronic lung infections of humans with cystic fibros
  • the infection may be caused by a drug-resistant strain of E. coli, the infection may present as a urinary tract infection.
  • the subject may be one that is hospitalized and/or is immunocompromised.
  • the treatment of a microbial infection in a subject in need thereof may also include further administering one or more antimicrobial agents, such as one or more antibiotics, to the subject as previously disclosed.
  • one or more antimicrobial agents such as one or more antibiotics
  • a class of compounds with a broad range of activity, particularly against bacteria is disclosed, and compositions including these compounds.
  • the compounds, which are further of this application, below, and compositions comprising one or more of the compounds, are presented herewith as a fourth aspect of the present disclosure.
  • the compounds and compositions comprising one or more of the compounds can be used to inhibit or reduce biofilm formation on a surface, treat or prevent an infection, and kill some antibiotic resistant organisms.
  • compounds and compositions comprising one or more of the compounds, and methods and uses employing one or more of the compounds and/or compositions, for inhibiting, reducing, or preventing biofilm formation or buildup on a surface or to removing, dispersing, reducing, or eradicating biofilm on a surface are disclosed.
  • compounds and compositions comprising one or more of the compounds, and methods and uses employing one or more of the compounds and/or compositions, for the treatment of, inhibition of growth of, and inhibition of colonization by, bacteria, both in biological and non-biological environments are also disclosed.
  • compounds and compositions comprising one or more of the compounds, and methods and uses employing one or more of the compounds and/or compositions, for the treatment of, inhibition of growth of, and inhibition of colonization by, bacteria, both in biological and non-biological environments are also disclosed.
  • compounds and compositions comprising one or more of the compounds, and methods and uses employing one or more of the compounds and/or compositions, for disinfecting surfaces, both in biological and non- biological environments, and products that have been coated with, or treated by, one or more of the compounds and/or compositions are further disclosed.
  • compounds and compositions comprising one or more of the compounds, and methods and uses employing one or more of the compounds and/or compositions, for potentiating the effects of one or more antibiotics, increasing the sensitivity of bacteria (including antibiotic- resistant bacteria) to one or more antibiotics, and also to reversing antibiotic resistance in bacteria are disclosed.
  • compounds and compositions comprising one or more of the compounds, and methods and uses employing one or more of the compounds and/or compositions, for enhancing the growth of animals and their efficiency of feed utilization, in particular by oral administration of feed and drink compositions are disclosed.
  • compositions comprising, consisting essentially of, or consisting of, one or more of these compounds is also provided. These compositions may be used in all of the other various aspects, and methods and uses disclosed above which employ the compositions, and may comprise, consist essentially of, or consist of, one or more types of compound as defined in this section, including derivatives and salts as defined in sub-sections 1 and 2, respectively.
  • compounds of particular interest for use in accordance with the present invention include Fe III complexes comprising ligands bound to the iron centre selected from amino acids or a-hydroxy acids, including but not limited to ferric lactate (also referred to herein as Fe- Lac), ferric citrate (also referred to herein as Fe-Cit), ferric tartarate (also referred to herein as Fe-Tart), ferric glycinate (also referred to herein as Fe- Gly), ferric quinate (also referred to herein interchangeable as FeQ and Fe- QA), complexes of tyrosine with ferric ion such as ferric tyrosine (also referred to herein as FeTyr), complexes of ferric ion with DOPA (also referred to herein as FeDOPA), and the complex of ferric ion with phenylalanine (also referred to herein as Fe-Phe).
  • ferric lactate also referred to herein as Fe- Lac
  • Fe-Cit ferric tart
  • the ligands that may be used in such complexes include ligands based on amino acids, a-hydroxy acids, o-hydroxy benzoic acids or pyridine- 2-carboxylic acids.
  • Exemplary amino acids can include, but are not limited to alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, each preferably in the L-isoform although, as discussed above, in an alternative embodiment one or more (optionally all) may be in the D-isoform. Mixtures of optical isomers of the same amino acid may, or may not, be used in some embodiments.
  • Exemplary a-hydroxy acids include, but are not limited to, quinic acid, lactic acid, glycolic acid, citric acid, tartaric acid, malic acid, and mandelic acid.
  • Exemplary o-hydroxy benzoic acids include, but are not limited to, salicylic acid.
  • Exemplary pyridine-2-carboxylic acids include, but are not limited to, oc-Picolinic acid.
  • compounds are Fe III complexes, which may optionally bind to MOMPs or FlaA of Campylobacter, wherein the Fe III complexes are represented by the following chemical Formula I:
  • each ligand present is independently a conjugate base of a substituted or unsubstituted a-hydroxy acid selected from citric acid, malic acid, tartaric acid, lactic acid, glycolic acid, quinic acid, glycolic, isoleucic, valic, and mandelic acid; and salts and/or hydrates thereof.
  • all the ligands are the same.
  • the a-hydroxy acids listed may contain more than one carboxylic acid moiety and the term conjugate base as used herein refers to acids having at least one acidic group in a deprotonated form. In some embodiments, all the acidic groups of an a-hydroxy acid derived ligand may be deprotonated.
  • the one or more ligands present are independently a conjugate base of a substituted or unsubstituted amino acid selected from the group consisting of glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine,
  • phenylalanine proline, serine, threonine, tryptophan, tyrosine, and valine, wherein x and y are as previously defined; and salts and/or hydrates thereof.
  • the ratio of x:y is such that the total charge of the Fe III complexes is neutral.
  • the ligands described above are bidentate or tridentate ligands which complex the Fe(III) ion.
  • the total charge of the Fe III complexes may be neutral due to the presence of an anion or cation, such as, but not limited to, hydroxide, chloride, sodium, potassium, or lithium ion.
  • the Fe complexes may crystallize incorporating one or more molecules of base.
  • Exemplary compounds of Fe complexes according to Formula I include, but are not limited to, the compounds shown below:
  • ferric lactate (denoted Fe-Lac)
  • ferric citrate (denoted Fe-Cit)
  • the compounds which may bind to MOMPs or FlaA of Campylobacter are Fe III complexes each containing three bidentate ligands, such as described herein.
  • a compound according to Formula I may be a compound that inhibits biofilm formation by bacteria as measured in a plastic bead, wherein the bacteria is grown in a medium containing the compound to form a growth suspension of the bacteria at 0.0001 OD/ml, the growth suspension is allowed to grow with plastic coated UV beads
  • the beads are assayed after 24 hours for the presence of biofilm formation on the beads (by counting bacteria after release from the beads), and compared to a control group where the bacteria is not grown in the presence of the compound.
  • the compound inhibits the binding of the bacteria to the plastic coated beads at a level of inhibition that is at, or at least, about 1%, 2%, 3%, 4%, more preferably at, or at least, about 5%, even more preferably at, or at least, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of the level of inhibition of the binding of the bacteria to the plastic coated UV beads by either a complex of L-tyrosine with Fe III or a complex of quinic acid with Fe III at the same molar concentration.
  • the bacteria can be Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, Campylobacter jejuni, Pseudomonas aeruginosa, Uropathogenic Escherichia coli, and Enteropathogenic Escherichia coli.
  • a compound according to Formula I may be a compound that inhibits binding of Helicobacter pylori to human gastric tissue (for example as determined by a method as described in Example 5) at a level of inhibition that is at, or at least, about 1%, 2%, 3%, 4%, more preferably at, or at least, about 5%, even more preferably at, or at least, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of the level of inhibition of the binding of the bacteria to human gastric tissue by either a complex of L-tyrosine with Fe III or a complex of quinic acid with Fe III at the same molar concentration as measured by counting the average number of bacteria bound to the tissue.
  • a compound according to Formula I may be a compound that inhibits biofilm formation of a bacteria, but does not inhibit planktonic growth of the bacteria, wherein the bacteria can be one or more of the following: Enterococcus faecalis, Staphylococcus epidermidis,
  • the compounds inhibit biofilm formation (for example, as measured by coverage rate in Example 7), at a level that is at, or at least, about 1%, 2%, 3%, 4%, more preferably at, or at least, about 5%, even more preferably at, or at least, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of the level of biofilm inhibition by a complex of L-tyrosine with Fe III or a complex of quinic acid with Fe III at the same molar concentration.
  • a compound according to Formula I may be a compound that prevents attachment of bacteria to a surface, and the prevention of attachment of bacteria to the surface is at a level that is at, or at least, about 1%, 2%, 3%, 4%, more preferably at, or at least, about 5%, even more preferably at, or at least, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of the level of bacteria attachment by a complex of L-tyrosine with Fe III or a complex of quinic acid with Fe III at the same molar concentration as measured by optical density.
  • the bacteria can be Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, Campylobacter jejuni, Pseudomonas aeruginosa, Uropathogenic Escherichia coli, and Enteropathogenic Escherichia coli.
  • a compound according to Formula I may be a compound that is capable of rendering an antibiotic resistant strain of bacteria sensitive to the antibiotic to which it is otherwise resistant (for example, when determined by a method that comprises immersing a patch in a solution of the compound and an antibiotic, such as kanamycin, for example at a concentration of 50 pg/mL as described in Example 9, placed on a plate with the antibiotic resistant strain (such as a kanamycin resistant strain of Enteropathogenic Escherichia coli or Campylobacter jejuni)), and causes the bacteria to fail to grow or reduces the rate of growth of the antibiotic resistant strain in the presence of the antibiotic by a level that is a level that is at, or at least, about 1%, 2%, 3%, 4%, more preferably at, or at least, about 5%, even more preferably at, or at least, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or
  • a compound according to Formula I for may be a compound that causes a decrease in the rate of growth to a level that is at, or at least, about 1%, 2%, 3%, 4%, more preferably at, or at least, about 5%, even more preferably at, or at least, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of the decrease in the rate of growth measured by optical density of an antibiotic resistant bacteria when grow in the presence of the compound and the antibiotic.
  • the one or more compounds instead of the direct administration of the one or more compounds, it or they may be formed in vivo, by administering a suitable iron containing substance and one or more suitable ligands capable of forming the compounds in vivo with the iron compound (see: Campbell and Hasinoff, Ferrous sulfate reduces levodopa bioavailability: Chelation as a possible mechanism, Clin. Pharmacol. Ther. 45:220-5, 1989).
  • ferrous sulfate and tyrosine may be administered in order to form Fe-Tyr in vivo
  • ferrous sulfate and L-DOPA (as ligand) may be administered in order to form Fe-DOPA in vivo
  • ferrous sulfate and L-phenylalanine (as ligand) may be administered in order to form Fe-Phe in vivo
  • ferrous sulfate and quinic acid (as ligand) may be administered in order to from Fe-QA in vivo.
  • Fe 2+ is oxidized to Fe 3+ in vivo, and may complex with tyrosine, L-DOPA, or phenylalanine respectively.
  • the compounds may also be formed in vivo from any substance that can be metabolized in vivo to the compounds.
  • phenylalanine could be administered with ferrous sulfate since it will be metabolized to tyrosine in vivo, and may then complex with the ferric iron (formed from oxidation of ferrous sulfate).
  • ferric chloride could also be administered with, for example, tyrosine, quinic acid, L-DOPA and/or phenylalanine.
  • one or more compounds for use in any of the first, methods disclosed above are ligands for the major outer membrane proteins (MOMPs) or FlaA of Campylobacter, and/or may be capable of downregulating the expression of FlaA and/or FlaB proteins in a bacteria such as
  • Campylobacter such as to the extent of causing a reduced bacterial motility such as when determined by a method as described in Example 21 of the present application.
  • the binding of the compounds to the MOMPs or FlaA inhibits the MOMPs or FlaA from attaching, binding, or associating with other proteins, biofilm components, surfaces or other bacteria.
  • the compound can be a mimetic or synthetic human histo-blood group antigen or a synthetic sugar.
  • a synthetic human histo-blood group antigen may be a sugar, for example a saccharide having the same structure as a natural human histo-blood group antigen such as for example H-I antigen, H-II antigen, Lewis antigen, Le b , Le x or Le y .
  • a preferred compound is ferric quinate (Fe-QA).
  • the compounds provided herein which bind to MOMPs or FlaA of Campylobacter include compounds with structures described in this section, in accordance with Formulae A or B, or further compounds as described below. It has been demonstrated that these compounds inhibit both gram negative bacteria, such as Pseudomonas aeruginosa, Campylobacter jejuni, Helicobacter pylori, Escherichia coli, Enteropathogenic Escherichia coli (EPEC), Uropathogenic Escherichia coli (UPEC) and gram positive bacteria, such as Staphylococcus epidermidis, Staphylococcus aureus, and
  • Campylobacter and other bacteria It is believed that the compounds interact with several surface porin-like bacterial proteins that have not yet been identified on other bacteria.
  • a composition comprising an Fe III complex as described above it may be that less than 100% of the Fe III ligands are identical, although preferably at least 50%, 60%, 70%, 80%, 85%, 90%,
  • the term “identical” discriminates between enantiomeric forms of ligand, that is, different enantiomers are not identical; whereas, in another embodiment, the term“identical” can be applied to different enantiomeric forms of ligand, that is, optionally different enantiomeric forms of the same ligand are considered to be identical.
  • Derivatives of the compounds may also be used.
  • the term “derivative” does not mean that the derivative is synthesized from the parent compound either as a starting material or intermediate, although this may be the case.
  • the term“derivative” can include salts (for example,
  • Derivatives include compounds in which free amino groups in the parent compound have been derivatized to form amine hydrochlorides, p- toluene sulfoamides, benzoxycarboamides, t-butyloxycarboamides, thiourethane-type derivatives, trifluoroacetylamides, chloroacetylamides, or formamides.
  • Derivatives include compounds having one or more amino substituents or hydrogen groups replaced with substituted or unsubstituted alkyl, aminoalkyl, aryl, or heteroaryl groups having from 1 to 30 carbon atoms.
  • the compounds of the Formulae described herein can be in the form of a salt, for example, a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids and inorganic or organic bases.
  • Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts, and bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide and ammonium hydroxide.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and n
  • the pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704; and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” P. Heinrich Stahl and Camille G. Wermuth, Eds., Wiley-VCH, Weinheim, 2002.
  • Antimicrobial agents that may be used therapeutically and/or non- therapeutically with the compounds disclosed herein above, for example for the treatment or prophylaxis of microbial infection in the methods disclosed above either separately, simultaneously or sequentially, include, but are not limited to: (i) Aminoglycosides, including amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin,
  • spectinomycin (ii) Ansaycins, including geldanamycin, herbimycin, rifaximin, (iii) Carbacephem, including loracarbef, (iv) Carbapenems, including ertapenem, doripenem, imipenem/cilastatin, meropenem, (v) Cephalosporins, including cefadroxil, cefazolin, cefalotin or cefalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobiprole, (vi) Glycopep tides
  • quinupristin/dalfopristin quinupristin/dalfopristin, thiamphenicol, tigecycline, tinidazole, and trimethoprim; and combinations thereof.
  • the compounds may also be combined with triclosan and chlorhexidine.
  • Other antimicrobial agents include: aztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin and its sodium salt; cefazolin and its sodium salt; cefaclor; ceftibuten and its sodium salt; ceftizoxime; ceftizoxime sodium salt; cefoperazone and its sodium salt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil; ceftazidime and its sodium salt; cephalexin; cefamandole nafate; ce
  • carbenicillin and its disodium or indanyl disodium salt piperacillin and its sodium salt; ticarcillin and its disodium salt; sulbactam and its sodium salt; moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin;
  • gatifloxacin trovafloxacin mesylate; alatrofloxacin mesylate; trimethoprim; sulfamethoxazole; demeclocycline and its hydrochloride, sulfate, or phosphate salt; doxycycline and its hydrochloride, sulfate, or phosphate salt; oxytetracycline and its hydrochloride, sulfate, or phosphate salt;
  • chlortetracycline and its hydrochloride, sulfate, or phosphate salt
  • metronidazole metronidazole; dapsone; atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride, sulfate, or phosphate salt; sulfacetamide and its sodium salt; clarithromycin; and silver ions, salts, and complexes.
  • the compounds above can be formulated for use in any of the methods disclosed above, and may, for example, be formulated in a way that is suitable for enteral, parenteral, topical, or pulmonary administration.
  • the compounds above can be combined with one or more pharmaceutically acceptable carriers and/or excipients that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • the carrier can include all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • the compounds are included in the formulation in an effective amount to achieve the desired effect, for example in an amount that is effective to inhibit biofilm formation or reduce biofilm buildup.
  • An effective amount of a compound provided to a subject may be an amount that is enough to provide the required degree of reduction of microbial colonization. This may depend on the type of compound and/or the size of the animal.
  • an effective amount of the compound may be an amount that is effective to deliver the compound to the site at which action is required in a concentration that ranges from 1 pm to 1 M, preferably greater than 10 mM, 20mM, 30mM, 40 mM, 50 mM , 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120mM, 130mM, 140 mM, 150 mM , 160 mM, 170 mM, 180 mM, 190 mM, 200 mM or more.
  • a suitable concentration may be within the range of about Imih to about 1 mM, or about 30mhi to about 0.5 mM, or about 60 mM to about 0.3 mM. These concentrations may particularly apply in the context of the second and/or third aspects of the present disclosure..
  • an effective amount of the compound may be 0.3 to 32 mg/day/kg bodyweight of the subject such as a chicken. In another embodiment an effective concentration of the compound may be between 0.001 to 1 mM for use in coatings or devices, or solutions.
  • the compounds can also be formulated for use as a disinfectant, for example, in a hospital environment or for industrial application.
  • the compounds above may be formulated for parenteral
  • Parenteral administration may include administration to a patient intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally,
  • intratracheally intravitreally, intratumorally, intramuscularly, subcutaneously, subconjunctivally, intravesicularly, intrapericardially, intraumbilically, by injection, and by infusion.
  • Parenteral formulations can be prepared as aqueous compositions using techniques known in the art.
  • such compositions can be prepared as injectable formulations, for example, solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection; emulsions, such as water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and
  • microemulsions thereof, liposomes, or emulsomes are examples of microemulsions thereof, liposomes, or emulsomes.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof.
  • polyols e.g., glycerol, propylene glycol, and liquid polyethylene glycol
  • oils such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.)
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants.
  • isotonic agents for example, sugars or sodium chloride.
  • Solutions and dispersions of the active compounds as the free acid or base or pharmacologically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, viscosity modifying agents, and combination thereof.
  • Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium ions of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® (triblock copolymer of polyoxyethylene, followed by a block of polyoxypropylene, followed by a block of polyoxyethylene) 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate,
  • amphoteric surfactants include sodium N-dodecyl-.beta.- alanine, sodium N - 1 a u r y 1 - b - i m i n od i p ro p i o n a te , myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.
  • the formulation may also contain an antioxidant to prevent degradation of the active agent(s).
  • the formulation is typically buffered to a pH of 3-8 for parenteral administration upon reconstitution.
  • Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers. It is to be noted that FeQ and some of the other compounds of the application are acidic, and so advantageously are formulated with a buffer in order to achieve a suitable pH, particularly in the context of preparing injectable formulation, including formulations for intravenous injection.
  • Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.
  • Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art.
  • parenteral formulations described herein comprising one or more compounds above may be formulated for controlled release including immediate release, delayed release, extended release, pulsatile release, and combinations thereof.
  • the one or more compounds and optionally one or more additional active agents can be incorporated into microparticles, nanoparticles, or combinations thereof that provide controlled release of the compounds and/or one or more additional active agents.
  • the formulations contains two or more active components, such as drugs, then they can be formulated for the same type of controlled release (e.g., delayed, extended, immediate, or pulsatile) or they can be independently formulated for different types of release (e.g., immediate and delayed, immediate and extended, delayed and extended, delayed and pulsatile, etc.).
  • the compounds and/or one or more additional active agents can be incorporated into polymeric microparticles, which provide controlled release of the active agent(s). Release of the active agent (s) is controlled by diffusion of the drug(s) out of the microparticles and/or degradation of the polymeric particles by hydrolysis and/or enzymatic degradation.
  • Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives.
  • Polymers which are slowly soluble and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide, can also be suitable as materials for drug containing microparticles.
  • Other polymers include, but are not limited to, poly anhydrides, poly(ester anhydrides), polyesters, such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone, poly-3 -hydroxybutyrate (PHB) and copolymers thereof, poly-4-hydroxybutyrate (P4HB) and copolymers thereof, polycaprolactone and copolymers thereof, polymers including, but not limited to, polymers of glycolic acid, lactic acid, 1,4- dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, 4- hydroxybutyrate, e-caprolactone, including polyglycolic acid, polylactic acid, polydioxanone, polycaprolactone,
  • polycyanoacrylates poly(oxyethylene)/poly(oxypropylene) copolymers ; polyacetals, polyketals; polyphosphates; (phosphorous-containing) polymers; polyphosphoesters; polyalkylene oxalates; polyalkylene succinates;
  • PEG polyethylene glycol
  • PVP polyvinyl pyrrolidone
  • the active agent can be incorporated into microparticles prepared from materials which are insoluble in aqueous solution or slowly soluble in aqueous solution, but are capable of degrading within the GI tract by means including enzymatic degradation, surfactant action of bile acids, and/or mechanical erosion.
  • the term“slowly soluble in water” refers to materials that are not dissolved in water within a period of 30 minutes. Preferred examples include fats, fatty substances, waxes, wax like substances and mixtures thereof.
  • Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol), fatty acids and derivatives, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides), and hydrogenated fats.
  • fatty alcohols such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol
  • fatty acids and derivatives including but not limited to fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides), and hydrogenated fats.
  • Specific examples include, but are not limited to hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oils available under the trade name STEROTEX®, stearic acid, cocoa butter, and stearyl alcohol.
  • Suitable waxes and wax-like materials include natural or synthetic waxes, hydrocarbons, and
  • waxes include beeswax, glycowax, castor wax, camauba wax, paraffins and candelilla wax.
  • a wax-like material is defined as any material, which is normally solid at room temperature and has a melting point of from about 30 to 300°C.
  • rate-controlling (wicking) agents can be formulated along with the fats or waxes listed above.
  • rate-controlling materials include certain starch derivatives (e.g., waxy maltodextrin and drum dried com starch), cellulose derivatives (e.g., hydroxypropylmethyl-cellulose, hydroxypropylcellulose,
  • a pharmaceutically acceptable surfactant for example, lecithin
  • Proteins, which are water insoluble, such as zein, can also be used as materials for the formation of active agent containing microparticles.
  • proteins, polysaccharides and combinations thereof, which are water-soluble can be formulated with drug into microparticles and subsequently cross-linked to form an insoluble network.
  • cyclodextrins can be complexed with individual drug molecules and subsequently cross-linked.
  • Encapsulation or incorporation of active agent, such as the one or more compounds into carrier materials to produce drug-containing microparticles can be achieved through known pharmaceutical formulation techniques.
  • the carrier material is typically heated above its melting temperature and the active agent is added to form a mixture comprising active agent particles suspended in the carrier material, active agent dissolved in the carrier material, or a mixture thereof.
  • Microparticles can be subsequently formulated through several methods including, but not limited to, the processes of congealing, extrusion, spray chilling or aqueous dispersion.
  • wax is heated above its melting temperature, active agent is added, and the molten wax-drug mixture is congealed under constant stirring as the mixture cools.
  • the molten wax-drug mixture can be extruded and spheronized to form pellets or beads.
  • active agent-containing microparticles For some carrier materials it may be desirable to use a solvent evaporation technique to produce active agent-containing microparticles.
  • active agent and carrier material are co-dissolved in a mutual solvent and microparticles can subsequently be produced by several techniques including, but not limited to, forming an emulsion in water or other appropriate media, spray drying or by evaporating off the solvent from the bulk solution and milling the resulting material.
  • active agent in a particulate form is homogeneously dispersed in a water-insoluble or slowly water soluble material.
  • the active agent powder itself may be milled to generate fine particles prior to formulation. The process of jet milling, known in the pharmaceutical art, can be used for this purpose.
  • active agent in a particulate form is homogeneously dispersed in a wax or wax like substance by heating the wax or wax like substance above its melting point and adding the active agent particles while stirring the mixture.
  • a pharmaceutically acceptable surfactant may be added to the mixture to facilitate the dispersion of the active agent particles.
  • the particles can also be coated with one or more modified release coatings.
  • Solid esters of fatty acids which are hydrolyzed by lipases, can be spray coated onto microparticles or active agent particles.
  • Zein is an example of a naturally water-insoluble protein. It can be coated onto active agent containing microparticles or active agent particles by spray coating or by wet granulation techniques.
  • some substrates of digestive enzymes can be treated with cross- linking procedures, resulting in the formation of non-soluble networks.
  • cross-linking proteins Many methods of cross-linking proteins, initiated by both chemical and physical means, have been reported.
  • One of the most common methods to obtain cross-linking is the use of chemical cross-linking agents.
  • chemical cross-linking agents include aldehydes (gluteraldehyde and formaldehyde), epoxy compounds, carbodiimides, and genipin.
  • aldehydes gluteraldehyde and formaldehyde
  • epoxy compounds epoxy compounds
  • carbodiimides genipin.
  • oxidized and native sugars have been used to cross-link gelatin.
  • Cross-linking can also be accomplished using enzymatic means; for example, transglutaminase has been approved as a GRAS substance for cross-linking seafood products.
  • cross-linking can be initiated by physical means such as thermal treatment, UV irradiation and gamma irradiation.
  • a water-soluble protein can be spray coated onto the microparticles and subsequently cross- linked by the one of the methods described above.
  • active agent-containing microparticles can be microencapsulated within protein by coacervation-phase separation (for example, by the addition of salts) and subsequently cross-linked.
  • suitable proteins for this purpose include gelatin, albumin, casein, and gluten.
  • Polysaccharides can also be cross-linked to form a water-insoluble network. For many polysaccharides, this can be accomplished by reaction with calcium salts or multivalent cations, which cross-link the main polymer chains. Pectin, alginate, dextran, amylose and guar gum are subject to cross- linking in the presence of multivalent cations. Complexes between oppositely charged polysaccharides can also be formed; pectin and chitosan, for example, can be complexed via electrostatic interactions.
  • the one or more compounds above can be incorporated into injectable/implantable solid or semi-solid implants, such as polymeric implants.
  • the compounds are incorporated into a polymer that is a liquid or paste at room temperature, but upon contact with aqueous medium, such as physiological fluids, exhibits an increase in viscosity to form a semi-solid or solid material.
  • Exemplary polymers include, but are not limited to, hydroxyalkanoic acid polyesters derived from the copolymerization of at least one unsaturated hydroxy fatty acid copolymerized with hydroxyalkanoic acids. The polymer can be melted, mixed with the active substance and cast or injection molded into a device.
  • Such melt fabrication requires polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive.
  • the device can also be prepared by solvent casting where the polymer is dissolved in a solvent and the drug dissolved or dispersed in the polymer solution and the solvent is then evaporated. Solvent processes require that the polymer be soluble in organic solvents.
  • Another method is compression molding of a mixed powder of the polymer and the drug or polymer particles loaded with the active agent.
  • the compounds can be incorporated into a polymer matrix and molded, compressed, or extruded into a device that is a solid at room temperature.
  • the compounds can be incorporated into a biodegradable polymer, such as poly anhydrides, polyhydroalkanoic acids (PHAs), PLA, PGA, PLGA, polycaprolactone, polyesters, polyamides, polyorthoesters, polyphosphazenes, proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin, and combinations thereof and compressed into solid device, such as disks, or extruded into a device, such as rods.
  • a biodegradable polymer such as poly anhydrides, polyhydroalkanoic acids (PHAs), PLA, PGA, PLGA, polycaprolactone, polyesters, polyamides, polyorthoesters, polyphosphazenes, proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin, and combinations thereof and compressed into solid device, such as disks, or extruded into a device, such as rods.
  • polymers for use in this context include polymers include, but are not limited to, polymers of glycolic acid, lactic acid, 1,4- dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, 4- hydroxybutyrate, e-caprolactone, including polyglycolic acid, polylactic acid, polydioxanone, polycaprolactone, copolymers of glycolic and lactic acids, such as VICRYL® polymer, MAXON® and MONOCRYL® polymers, and including poly(lactide-co-caprolactones); poly(orthoesters); polyanhydrides; poly(phosphazenes); polyhydroxyalkanoates; synthetically or biologically prepared polyesters; polycarbonates; tyrosine polycarbonates; polyamides (including synthetic and natural polyamides, polypeptides, and poly(amino acids)); polyesteramides; poly(alkylene alkylates); poly ethers (such as polyethylene glycol, PEG, and polyethylene oxide
  • polycyanoacrylates poly(oxyethylene)/poly(oxypropylene) copolymers ; polyacetals, polyketals; polyphosphates; (phosphorous-containing) polymers; polyphosphoesters; polyalkylene oxalates; polyalkylene succinates;
  • PEG polyethylene glycol
  • PVP polyvinyl pyrrolidone
  • the release of the one or more compounds from the implant can be varied by selection of the polymer, the molecular weight of the polymer, and/or modification of the polymer to increase degradation, such as the formation of pores and/or incorporation of hydrolyzable linkages.
  • Methods for modifying the properties of biodegradable polymers to vary the release profile of the compounds from the implant are well known in the art.
  • the compounds above may be formulated for enteral administration.
  • Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups, and lozenges. Tablets can be made using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can be prepared as hard or soft capsule shells, which can encapsulate liquid, solid, and semi-solid fill materials, using techniques well known in the art.
  • Formulations may be prepared using a pharmaceutically acceptable carrier.
  • carrier includes, but is not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.
  • Carrier also includes all components of the coating composition, which may include plasticizers, pigments, colorants, stabilizing agents, and glidants.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.
  • cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate
  • polyvinyl acetate phthalate acrylic acid polymers and copolymers
  • methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), ze
  • the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • “Diluents”, also referred to as “fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose,
  • microcrystalline cellulose kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture.
  • suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (POLYPLASDONE® XL from GAF Chemical Corp).
  • starch sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (POLYPLASDONE® XL from GAF Chemical Corp).
  • Stabilizers are used to inhibit or retard drug decomposition reactions, which include, by way of example, oxidative reactions. Suitable stabilizers include, but are not limited to, antioxidants, butylated
  • BHT hydroxytoluene
  • Vitamin E tocopherol and its salts
  • sulfites such as sodium metabisulphite
  • cysteine and its derivatives citric acid
  • propyl gallate and butylated hydroxyanisole (BHA).
  • Oral dosage forms such as capsules, tablets, solutions, and suspensions, can be formulated for controlled release, for example, for the controlled release of the one or more compounds above.
  • the one or more compounds and optional one or more additional active agents can be formulated into nanoparticles, microparticles, and combinations thereof, and encapsulated in a soft or hard gelatin or non-gelatin capsule or dispersed in a dispersing medium to form an oral suspension or syrup.
  • the particles can be formed of the active agent and a controlled release polymer or matrix.
  • the active agent particles can be coated with one or more controlled release coatings prior to incorporation in to the finished dosage form.
  • the one or more compounds and optional one or more additional active agents are dispersed in a matrix material, which gels or emulsifies upon contact with an aqueous medium, such as physiological fluids.
  • aqueous medium such as physiological fluids.
  • the matrix swells entrapping the active agents, which are released slowly over time by diffusion and/or degradation of the matrix material.
  • Such matrices can be formulated as tablets or as fill materials for hard and soft capsules.
  • the one or more compounds, and optional one or more additional active agents are formulated into a sold oral dosage form, such as a tablet or capsule, and the solid dosage form is coated with one or more controlled release coatings, such as a delayed release coatings or extended release coatings.
  • the coating or coatings may also contain the compounds and/or additional active agents.
  • the extended release formulations are generally prepared as diffusion or osmotic systems, which are known in the art.
  • a diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds.
  • Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and CARBOPOL® 934 (cross-linked polyacrylate polymer), polyethylene oxides and mixtures thereof.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
  • the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly (methacrylic acid), methacrylic acid alkylamine copolymer poly (methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate, aminoalky
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the tradename EUDRAGIT®.
  • the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names EUDRAGIT® RL30D and EUDRAGIT ® RS30D, respectively.
  • EUDRAGIT® RL30D and EUDRAGIT ® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT ® RL30D and 1:40 in EUDRAGIT® RS30D.
  • the mean molecular weight is about 150,000.
  • EUDRAGIT ® S- 100 and EUDRAGIT ® L-100 are also preferred.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • EUDRAGIT ® RL/RS mixtures are insoluble in water and in digestive fluids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the polymers described above such as EUDRAGIT ® RL/RS may be mixed together in any desired ratio in order to ultimately obtain a sustained- release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems may be obtained, for instance, from 100% EUDRAGIT® RL, 50% EUDRAGIT® RL and 50%
  • EUDRAGIT t® RS and 10% EUDRAGIT® RL and 90% EUDRAGIT®
  • extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form.
  • the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion.
  • the devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units.
  • multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads, or granules.
  • An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar.
  • Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose.
  • Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used.
  • Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders.
  • a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method.
  • the congealing method the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed.
  • Delayed release formulations can be created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine.
  • the delayed release dosage units can be prepared, for example, by coating an active agent or an active agent -containing composition with a selected coating material.
  • the active agent -containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core” dosage form, or a plurality of active agent -containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers.
  • Enteric polymers as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon.
  • Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename EUDRAGIT® (Rohm Pharma; Westerstadt, Germany), including
  • EUDRAGIT® L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT® L-100 (soluble at pH 6.0 and above), EUDRAGIT® S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and EUDRAGITS® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied.
  • the preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies.
  • the coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
  • a plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 3 wt. % to 50 wt. or 10 wt% to 50 wt.%, relative to the dry weight of the polymer.
  • typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution.
  • One effective glidant is talc.
  • Other glidants such as magnesium stearate and glycerol monostearates may also be used.
  • Pigments such as titanium dioxide may also be used.
  • Small quantities of an anti foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition.
  • the compounds as defined in section III. may be formulated for topical administration and use in the methods disclosed herein..
  • the formulations may contain the one or more compounds discussed above, alone or in combination, in an effective amount to prevent or inhibit biofilm formation on a surface, or reduce the amount of biofilm on a surface being treated. 1000 colony forming units (cfu) of Campylobacter are enough to infect a human and cause disease in a human.
  • an effective amount of the one or more compounds of this application is, or are, enough of the compound(s), alone, or in combination with other compounds, to reduce the number of cfu of Campylobacter or other microorganism of interest on the surface being treated to a number that is unlikely to, or which will not, cause infection in humans.
  • Suitable dosage forms for topical administration include creams, ointments, salves, sprays, gels, lotions, irrigants, and emulsions.
  • Buffers are used to control pH of a composition.
  • the buffers buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7.
  • the buffer is triethanolamine.
  • “Emollients” are an externally applied agent that softens or soothes skin and are generally known in the art and listed in compendia, such as the “Handbook of Pharmaceutical Excipients”, 4 th Ed., Pharmaceutical Press, 2003. These include, without limitation, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and combinations thereof. In one embodiment, the emollients are ethy
  • Emmulsifiers are surface active substances which promote the suspension of one liquid in another and promote the formation of a stable mixture, or emulsion, of oil and water. Common emulsifiers are: metallic soaps, certain animal and vegetable oils, and various polar compounds. Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides,
  • polyoxyethylene stearates polyoxyethylene stearates, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum and combinations thereof.
  • the emulsifier is glycerol stearate.
  • “Penetration enhancers” include, but are not limited to, fatty alcohols, fatty acid esters, fatty acids, fatty alcohol ethers, amino acids, phospholipids, lecithins, cholate salts, enzymes, amines and amides, complexing agents (liposomes, cyclodextrins, modified celluloses, and diimides), macrocyclics, such as macrocylic lactones, ketones, and anhydrides and cyclic ureas, surfactants, N-methyl pyrrolidones and derivatives thereof, DMSO and related compounds, ionic compounds, azone and related compounds, and solvents, such as alcohols, ketones, amides, polyols (e.g., glycols). Examples of these classes are known in the art.
  • Preservatives can be used to prevent the growth of fungi and microorganisms.
  • Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal.
  • “Surfactants” are surface- active agents that lower surface tension and thereby increase the emulsifying, foaming, dispersing, spreading and wetting properties of a product.
  • Suitable non-ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof.
  • the non-ionic surfactant is stearyl alcohol.
  • An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid.
  • the non-miscible components of the emulsion include a lipophilic component and an aqueous component.
  • the dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase.
  • oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil- in- water emulsion
  • water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase
  • water-in-oil emulsion water-in-oil emulsion.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol.
  • the oil phase may contain other oily
  • materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers.
  • the oil phase may consist at least in part of a propellant, such as an HFA propellant.
  • a propellant such as an HFA propellant.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • Preferred excipients include surfactants, especially non ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol.
  • the oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers.
  • a sub-set of emulsions are the self-emulsifying systems.
  • These delivery systems are typically capsules (hard shell or soft shell) comprised of the compound dispersed or dissolved in a mixture of surfactant(s) and lipophilic liquids such as oils or other water immiscible liquids.
  • capsules hard shell or soft shell
  • surfactant(s) and lipophilic liquids such as oils or other water immiscible liquids.
  • a lotion can contain finely powdered substances that are insoluble in the dispersion medium through the use of suspending agents and dispersing agents.
  • lotions can have as the dispersed phase liquid substances that are immiscible with the vehicle and are usually dispersed by means of emulsifying agents or other suitable stabilizers.
  • the lotion is in the form of an emulsion having a viscosity of between 100 and 1000 centistokes.
  • the fluidity of lotions permits rapid and uniform application over a wide surface area. Lotions are typically intended to dry on the skin leaving a thin coat of their medicinal components on the skin’s surface.
  • Creams may contain emulsifying agents and/or other stabilizing agents.
  • the formulation is in the form of a cream having a viscosity of greater than 1000 centistokes, typically in the range of 20,000- 50,000 centistokes. Creams are often time preferred over ointments, as they are generally easier to spread and easier to remove.
  • creams are typically thicker than lotions, may have various uses and often one uses more varied oils/butters, depending upon the desired effect upon the skin.
  • the water-base percentage is about 60-75 % and the oil-base is about 20-30 % of the total, with the other percentages being the emulsifier agent, preservatives and additives for a total of 100 %.
  • ointment bases include hydrocarbon bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil); absorption bases (hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointment), and water-soluble bases (e.g., polyethylene glycol ointments).
  • hydrocarbon bases e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil
  • absorption bases hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream
  • water-removable bases e.g., hydrophilic ointment
  • water-soluble bases e.g., polyethylene glycol ointments.
  • Pastes typically differ from ointments in that they contain a larger percentage of solids. Pastes are typically more absorptive and less greasy than ointments prepared with the same
  • Gels are semisolid systems containing dispersions of small or large molecules in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle.
  • the liquid may include a lipophilic component, an aqueous component or both.
  • Some emulsions may be gels or otherwise include a gel component.
  • Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components.
  • Suitable gelling agents include, but are not limited to, modified celluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol
  • Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alkylene glycols, such as propylene glycol; dimethyl isosorbide; alcohols, such as isopropyl alcohol and ethanol.
  • the solvents are typically selected for their ability to dissolve the compound.
  • Other additives, which improve the skin feel and/or emolliency of the formulation, may also be incorporated.
  • additives include, but are not limited to, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic triglycerides, and combinations thereof.
  • Foams include, but are not limited to, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic triglycerides, and combinations thereof.
  • Foams consist of an emulsion in combination with a gaseous propellant.
  • the gaseous propellant consists primarily of hydrofluoroalkanes (HFAs).
  • HFAs hydrofluoroalkanes
  • Suitable propellants include HFAs such as 1,1,1, 2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures and admixtures of these and other HFAs that are currently approved or may become approved for medical use are suitable.
  • the propellants preferably are not hydrocarbon propellant gases, which can produce flammable or explosive vapors during spraying.
  • the compositions preferably contain no volatile alcohols, which can produce flammable or explosive vapors during use.
  • the compounds above may be formulated into cleaning formulations.
  • the cleaning formulations include formulations that are highly efficacious for household cleaning applications (e.g., hard surfaces like floors, countertops, tubs, tile, dishes and softer cloth materials like clothing, sponges, paper towels, etc.), personal care applications (e.g. lotions, shower gels, soaps, shampoos, sprays, wipes, toothpaste, acne treatments, skin cleansers, mouthwash, wound irrigation solutions, towelettes, contact lenses and lens cases) and industrial and hospital applications (e.g., antifouling coatings, and disinfection of instruments, medical devices, gloves, filters, membranes, tubing, drains, pipes including gas pipes, oil pipes, drilling pipes, fracking pipes, sewage pipes, drainage pipes, hoses, animal carcasses, fish tanks, showers, children’s toys, boat hulls, and cooling towers). These formulations are efficacious for cleaning surfaces which are infected or contaminated with biofilm or for preventing the formation of biofilm on these surfaces.
  • personal care applications e.g. lotions, shower gels, soaps, shampoo
  • the compounds can be formulated into a solution in a suitable solvent for administration in a spray bottle, the compounds can be formulated as an aerosol, as a foam, suitable for spraying onto surfaces, or, they can be imbibed into a cloth or other item suitable for wiping down a surface to be disinfected.
  • Methods for making formulations for use as a disinfectant in the forms are known in the art.
  • One embodiment provides the compounds or a derivative thereof in a composition containing a pH dye indicator and an alkaline substance.
  • the pH indicator dye indicates what surface has been disinfected and ensures that a sufficient time has passed to disinfect the surface. See for example, U.S. Publication No. 20140057987.
  • Cleaning formulations can include the compounds and an acceptable carrier.
  • the carrier can be in a wide variety of forms.
  • the carrier may be an aqueous-based solution or cleanser, an alcohol-based solution or gel or an emulsion carrier, including, but not limited to, oil-in- water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions.
  • the carrier solution containing the compound(s) can be applied directly to the surface to be treated or delivered via a suitable substrate.
  • the cleaning formulations can be formulated for use on the skin.
  • the compounds can be formulate in a dermatologically acceptable carrier.
  • the dermatologically acceptable carriers can also be, for example, formulated as alcohol or water based hand cleansers, toilet bars, liquid soaps, shampoos, bath gels, hair conditioners, hair tonics, pastes, or mousses.
  • Cleaning formulations can contain one or more surfactants.
  • the surfactant is suitably selected from anionic, nonionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants.
  • Such surfactants are well known to those skilled in the detergency art.
  • Non limiting examples of possible surfactants include isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and sodium lauryl sulfate. Examples of a broad variety of additional surfactants are described in McCutcheon's Detergents and Emulsifiers. North American Edition (1986), published by Allured Publishing Corporation.
  • the cleansing formulations can optionally contain, at their art-established levels, other materials which are conventionally used in cleansing formulations.
  • Additional carriers suitable for the cleaning formulations may include various substrate-based products.
  • the present formulations may be impregnated into or onto the substrate products and may be allowed to remain wet or may be subjected to a drying process.
  • suitable carriers include, but are not limited to, dry and wet wipes suitable for personal care and household use (e.g., nonwoven baby wipes, household cleaning wipes, surgical preparation wipes, etc.); diapers; infant changing pads; dental floss; personal care and household care sponges or woven cloths (e.g., washcloths, towels, etc.); tissue-type products (e.g.
  • Cleaning formulations can be incorporated into various household care products including, but not limited to, hard surface cleaners (e.g., disinfectant sprays, liquids, or powders); dish or laundry detergents (liquid or solid), floor waxes, glass cleaners, etc.
  • hard surface cleaners e.g., disinfectant sprays, liquids, or powders
  • dish or laundry detergents liquid or solid
  • floor waxes glass cleaners, etc.
  • Exemplary carriers can include aqueous solutions, e.g. having from about 0% to about 98.8%, by weight of the composition, of water.
  • carriers may contain an aqueous alcohol solution.
  • the amount of alcohol present in the alcohol solution will vary depending on the type of product in which the composition is incorporated, i.e. say a wipe where the preferred amount of alcohol present would be from about 0% to about 25% whereas a hand sanitizer preferably contains from about 60% to about 95%, of alcohol. Therefore, suitable dermatologically acceptable alcohol solutions or gels may contain from about 0% to about 95%, by weight of the composition, of an alcohol.
  • Alcohols suitable for inclusion in the alcohol solutions of the carrier include, but are not limited to, monohydric alcohols, dihydric alcohols, and combinations thereof. More preferred alcohols are selected from the group consisting of monohydric linear or branched C2-C18 alcohols. The most preferred alcohols are selected from the group consisting of ethanol, isopropanol, n-propanol, butanol, and combinations thereof.
  • the cleaning formulations which contain an alcohol solution may be anhydrous or water containing. Thickeners can be added to the water or alcohol based to form a gel.
  • thickeners examples include, but are not limited to, naturally- occurring polymeric materials such as sodium alginate, xanthan gum, quince seed extract, tragacanth gum, starch, semi-synthetic polymeric materials such as cellulose ethers (e.g. hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose),
  • polyvinylpyrrolidone polyvinylalcohol, guar gum, hydroxypropyl guar gum, soluble starch, cationic celluloses, cationic guars and synthetic polymeric materials such as carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, and polyvinylidene chloride polymers.
  • Inorganic thickeners may also be used such as aluminum silicates, such as, for example, bentonites, or a mixture of polyethylene glycol and polyethylene glycol stearate or distearate.
  • the cleaning formulations can contain, in addition to the compounds described above, one or more antimicrobial or antifungal agents. Such agents are capable of destroying microbes, preventing the development of microbes or preventing the pathogenic action of microbes.
  • additional antimicrobial and antifungal agents include b-lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, 2,4,4'- trichloro-2'-hydroxy diphenyl ether (TRICLOSAN®), phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, clindamycin, ethambutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomycin, methacycline, met
  • Another class of antimicrobial agents which are useful, are the so-called "natural" antibacterial actives, referred to as natural essential oils.
  • Typical natural essential oil antibacterial actives include oils of anise, lemon, orange, rosemary, wintergreen, thyme, lavender, cloves, hops, tea tree, citronella, wheat, barley, lemongrass, cedar leaf, cedarwood, cinnamon, fleagrass, geranium, sandalwood, violet, cranberry, eucalyptus, vervain, peppermint, gum benzoin, basil, fennel, fir, balsam, menthol, ocmea origanum, Hydastis carradensis, Berberidaceae daceae, Ratanhiae and Curcuma longa.
  • the cleaning formulations may be packaged in a variety of suitable packaging known to those skilled in the art.
  • the liquid formulations may desirably be packaged in manually operated spray dispensing containers, which are usually made of synthetic organic polymeric plastic materials. Accordingly, disinfecting formulations containing the compounds and packaged in a spray dispenser, preferably in a trigger spray dispenser or a pump spray dispenser, are envisioned. Spray-type dispensers allow to uniformly apply to a relatively large area of a surface to be disinfected a liquid cleaning formulations described herein.
  • the compounds can be impregnated into a nonwoven absorbent wipe.
  • Disinfectant wet wipes are also disclosed for example in U.S. patent No. 8,563,017.
  • the compounds can be in an aqueous foam with a special surfactant system capable of generating a foam. See U.S. Patent No. 8,097,265, U.S. Patent No. 5,891,922 and U.S. Patent No. 4,889,645.
  • the compounds can also be in a pressurized spray aerosol. See also, U.S. Publication No. 20010053333 which discloses a liquid flash-dry aerosol disinfectant composition with a flash vaporization component and an effective amount of an antimicrobial agent.
  • the one or more compounds may be presented as conjugated and/or immobilized compounds.
  • the compounds may be conjugated with other agents in order to retain the compounds on surfaces, for example, to prevent biofilm formation on a surface.
  • the compounds may be conjugated to an agent that has affinity for a surface in order to retain the compounds on that surface.
  • the compounds may be conjugated to an agent wherein the agent is a polymer or oligomer, and the polymer or oligomer has a high affinity for the surface.
  • the compounds may be conjugated to an agent wherein the agent comprises a reactive moiety suitable for anchoring to a surface.
  • the reactive moiety may, for example, be photo-reactive, or capable of coupling covalently to a surface.
  • the reactive moiety may also incorporate spacers and linkers and other functional groups in order to place the compound in a desired location relative to the surface. Examples of how compound may be conjugated to an agent comprising a reactive moiety suitable for anchoring to a surface are shown below.
  • FeQ is conjugated to a calix[4] arene frame that comprises a reactive moiety.
  • FeQ is conjugated via a linker to a calix[4] arene frame that contains a photoreactive functional group.
  • a second example shows that the reactive moiety can be positioned at a different location on the calix[4] arene frame.
  • a third example shows FeQ conjugated to a calix[4] arene frame, wherein the latter is functionalized with thiol groups that are capable of reacting with surfaces. It should be understood that different linkers or no linkers may be used, and that other agents may be used instead of the calix[4] arene frame, including cyclodextrins and other polymers and oligomers.
  • the compounds may be conjugated to an agent that comprises a substance with an affinity for a surface.
  • the agent may incorporate spacers and linkers and other functional groups in order to place the compound in the desired location relative to the surface.
  • the agent contains hydroxyapatite.
  • the compounds may be conjugated via a linker to hydroxyapatite are shown below.
  • the linkers are attached in different positions to one of the quinic acid ligands via a functional group,
  • HA hydroxyapatite
  • X hydroxyapatite
  • the HA group may be replaced with a reactive group that can attach (or be attached) to a surface, such as a photo-reactive compound, isocyanate, hydroxy group, amine, trialkoxysilyl ether, such as a triethoxysilyl ether, or phosphate ester.
  • a reactive group that can attach (or be attached) to a surface
  • a reactive group such as a photo-reactive compound, isocyanate, hydroxy group, amine, trialkoxysilyl ether, such as a triethoxysilyl ether, or phosphate ester.
  • These groups may be attached directly to the polyethylene glycol, or an additional linker inserted between the reactive group and the polyethylene glycol.
  • the compounds can be formulated into growth promoting formulations, for example, in an animal feed or formula to improve the growth of the animal.
  • the one or more compounds may be added to drinking water for any of the animals to improve growth
  • the compounds may be useful in treatment of ponds, tanks, or other aquatic or marine environments containing fish (include freshwater and saltwater fish, farmed fish and ornamental fish), other marine and aquatic animals, including shellfish or crustaceans such as shrimp, oysters, mussels, clams, prawns, lobsters, crayfish, crabs, cuttlefish, octopus and crawfish.
  • fish include freshwater and saltwater fish, farmed fish and ornamental fish
  • other marine and aquatic animals including shellfish or crustaceans such as shrimp, oysters, mussels, clams, prawns, lobsters, crayfish, crabs, cuttlefish, octopus and crawfish.
  • the one or more compounds may be used alone or in combination with other anti-microbial, bactericidal or bacteriostatic compounds and/or growth enhancing agents.
  • the compounds can improve growth performance, and can be used to increase average body weight during growth.
  • the compounds can also be used to improve feed conversion ratio.
  • the compounds can be used to decrease the mortality adjusted feed conversion ratios (MFCR).
  • MFCR mortality adjusted feed conversion ratios
  • the compounds may be used to produce animals with higher average body weight in a given period of time, or may be used to reach a target average body weight in a shorter period of time.
  • the compounds may be used to decrease the amount of feed necessary for an animal to attain a target weight.
  • the compounds may be used in stressed environments to improve growth and MFCR. These environments include but are not limited to high stocking densities of animals, dirty pen litter, presence of pathogens, presence of Campylobacter and other bacteria, and high temperature environments.
  • compositions are particularly useful in feeds for commercial birds such as chickens, turkeys, pheasants, and ducks.
  • Exemplary poultry feeds in which the compounds can be included include poultry feeds that are referred to as "complete" feeds, because they are designed to contain all the protein, energy, vitamins, minerals, and other nutrients necessary for proper growth, egg production, and health of the birds. Feeding any other ingredients, mixed with the feed or fed separately, upsets the balance of nutrients in the "complete” feed. Feeding additional grain or supplement with the complete poultry feed is not recommended.
  • the one or more compounds of this application are particularly useful in promoting growth.
  • the compounds may be added to animal feed or animal drinking water in order to promote growth. Addition of the compounds to feed or drinking water results in improved growth. It has also been discovered that the compounds can be added to animal feed or animal drinking water in order to decrease the mortality adjusted feed conversion ratio. Thus it is possible to use the compounds to decrease the amount of feed necessary for an animal to grow.
  • the compounds may further be
  • the compounds are administered in feeds.
  • the compounds can be administered to animals that are in a stressed environment in order to improve their growth performance.
  • the compounds promote growth that yields animal with higher average body weights.
  • the compounds also decrease mortality adjusted feed conversion ratios in stressed environments.
  • Example 1 Efficacy of FeQ and FeTyr to reduce Campylobacter carriage in chickens and promote growth in chickens
  • Each treatment group comprised four replicates of 10 birds per pen (40 birds/treatment group and 4 pens of 10 birds/treatment group), with 2 control groups and 5 test groups. All the test groups and one of the control groups were exposed at day 20 of the trial to dirty litter, which tested positive for Campylobacter. This method was used to provide a more natural method to Campylobacter challenge the birds. Thus there was a positive control where one treatment group was challenged with
  • Treatment group 1 was a negative control where birds just received the commercial feed, and were not challenged with dirty litter containing Campylobacter.
  • Treatment group 2 was the positive control where the birds received the commercial feed, and were challenged with dirty litter containing Campylobacter at day 20.
  • Treatment group 3 received 0.22 g/L of FeQ in their drinking water and 0.22 g/Kg FeQ in their feed during the entire trial, and was challenged with dirty litter containing Campylobacter at day 20.
  • Treatment group 5 received 0.22 g/L of FeQ in their drinking water during the entire trial, and was challenged with dirty litter containing Campylobacter at day 20.
  • Treatment group 6 received 0.22 g/kg FeQ in their feed during the entire trial, and was challenged with dirty litter containing Campylobacter at day 20.
  • Treatment group 7 received 0.022 g/L FeQ in their drinking water during the entire trial, and was challenged with dirty litter containing Campylobacter at day 20.
  • Treatment group 8 received 0.02 g/L FeTyr in their drinking water during the entire trial, and was challenged with dirty litter containing Campylobacter at day 20.
  • the FeTyr was pre-dissolved in DMSO, and diluted to provide a solution of 0.02 g/L of FeTyr in water. (An additional treatment group 4 was terminated due to solubility issues.)
  • the birds were fed with a commercial three-phase feeding program using starter, grower and finisher feeds with formulations shown in Table 2 All diets had coccidiostat (MAXIBAN® at 0.0625% in starter and finisher phase diets and MONTEBAN® at 0.06% in finisher phase).
  • coccidiostat MAXIBAN® at 0.0625% in starter and finisher phase diets and MONTEBAN® at 0.06% in finisher phase.
  • Xylanase RONOZYME® WX at 200 g per ton
  • phytase RONOZYME® P at 150 grams per ton
  • each pen Prior to challenging the chickens with dirty litter containing Campylobacter at day 20, each pen was tested for Campylobacter using cloacal swabs. All pens tested negative for Campylobacter prior to the challenge.
  • litter which was naturally Campylobacter- contaminated, was tested to confirm the presence of Campylobacter, and then added (approximately 2 kg/pen) to the litter in all pens except in pens for treatment group 1 (the negative control).
  • the pen litter was sampled to confirm the presence or absence of Campylobacter.
  • caecal samples were taken from 3 birds per pen (12 birds per treatment group) and tested for Campylobacter enumeration.
  • digesta, fecal samples, and caecal content was taken from all birds, and pooled per pen. Two birds per pen were also taken from treatment groups 1- 3, euthanized, and blood samples taken. Samples were analyzed for blood chemistry, including analysis for alkaline phosphatase, aspartate amino transferase, alanine amino transferase, gamma-glutamyl transferase, lactate dehydrogenase, total protein, albumin, globulin, amylase and glucose.
  • Tables 4-13 show the effects on the treatment groups compared to the negative control group (treatment group 1) and the positive control group (treatment group 2) for the periods 0-11 days, 11-20 days, 20-25 days, 11-25 days, 25-42 days, 20-42 days, 0-20 days, and 0-42 days.
  • Figure 1 shows the average body weight at day 42 for all treatment groups, and a comparison to a commercial control labeled“Target”.
  • treatment group 1 the negative control labeled“CNC” attained an average body weight (ABW) of 3.437 kg at day 42 (which was higher than the commercial target of 2.979 kg).
  • the positive control (labeled “CC”), which was challenged with dirty litter containing Campylobacter at day 20, in contrast only attained an ABW of 3.186 kg at day 42, which was significantly less than the negative control (treatment group 1).
  • This result demonstrates that challenging with dirty litter contaminated with
  • Campylobacter resulted in a reduction of growth of the chicken by an average of 251 grams.
  • all treatment groups performed better than the positive control, demonstrating that FeQ and FeTyr treatment had a positive effect on growth.
  • FeQ in feed at 0.22 g/kg (treatment group 6) produced chicken with an ABW of 3.464 kg, which was higher than the negative control ABW of 3.437 kg even though treatment group 6 had been challenged with dirty litter containing Campylobacter.
  • Figure 2 shows the mortality adjusted feed conversion rate (MFCR) at day 42 for all treatment groups, and a comparison to a commercial control labeled“Target”. (A lower MFCR number is a better result.)
  • treatment group 1 the negative control labeled“CNC”
  • the positive control, labeled“CC” which was challenged with the dirty litter containing Campylobacter at day 20 had a significantly higher MFCR of 1.679 than the negative control.
  • MFCR mortality adjusted feed conversion rate
  • treatment groups 3, 5, 6, 7 and 8 all treatment groups performed better than the positive control demonstrating that FeQ and FeTyr treatment had a positive effect on MFCR (i.e. decreasing the numerical MFCR).
  • the results show that treatment groups 3, 5, 6, 7 and 8 had MFCR values of 1.595, 1.560, 1,563, 1.612 and 1.577, respectively.
  • treatment groups 5 and 6 performed as well as the negative control even when challenged with dirty litter containing Campylobacter.
  • Figure 3 shows the number of Campylobacter colony forming units per gram (cfu/g) of bird droppings at day 42 for treatment groups 1-3 and 6- 8. (A lower number is a better result.) The results show that treatment groups 3 and 6-8 all performed better than the positive control (treatment group 2) demonstrating that FeQ and FeTyr had a positive effect on reducing
  • Campylobacter infection of poultry Notably, chicken treated with FeTyr, FeQ in feed, and FeQ in feed and water all had colony forming units of Campylobacter per gram of dropping that were similar to, or less than, those of the negative control group (treatment group 1).
  • the detection of low levels of Campylobacter in the negative controls demonstrates how highly contagious the bacterium is, and is likely to be an indication that a small number of birds in the negative control group became infected despite not being experimentally challenged with dirty litter.
  • FIG. 4 confirm that treatment group 7 also had a highly beneficial effect.
  • Figure 4 shows the average number of Campylobacter colony forming units per gram (cfu/g) of caeca samples at day 42 for treatment groups 1-3 and 5-8. The results show that all the treatment groups (3 and 5-8) all performed better than the positive control (treatment group 2) demonstrating that FeQ and FeTyr had a positive effect on reducing
  • the average body weight (ABW) for the control groups (treatment groups 1 and 2) is 0.927 kg versus 0.963 kg for treatment groups 3, 5, 6 and 7 which all received FeQ. This improvement in body weight is also reflected in a significantly better MFCR for the FeQ treated birds.
  • Table 13 shows the MFCR for the birds treated in groups 3, 5, 6 and 7 is 1.2996 versus 1.3374 for the control groups (treatment groups 1 and 2).
  • the P- value is less than 0.05.
  • the AWG during the first 20 days of production for chicken treated with FeTyr (treatment group 8) is 0.895 kg compared to 0.884 and 0.889 kg for treatment groups 1 and 2 (negative and positive controls). Furthermore, the MFCR during the first 20 days of production for chicken treated with FeTyr (treatment group 8) is 1.311 versus 1.32 and 1.355 for treatment groups 1 and 2, respectively. (A lower MFCR value is an improvement.)
  • SED Standard errors of difference of means
  • ABW average body weight (kg)
  • AFD average feed intake (kg)
  • AWG average weight gain (kg);
  • MFCR Mortality adjusted FCR
  • FCR FCR commercial.
  • SED Standard errors of difference of means
  • ABW average body weight (kg)
  • AFD average feed intake (kg)
  • AWG average weight gain (kg);
  • MFCR Mortality adjusted FCR
  • FCR FCR commercial.
  • Example 2 Fe-Lac Prevention of biofilm formation by Pseudomonas aeruginosa.
  • the slides were removed from bacterial culture and washed with 15 mL phosphate buffered saline at room temperature for 5 minutes three times and then rinsed with distilled FLO. After washing, the slides were stained with 20 mM SYT017 dye (Invitrogen, UK) at room temperature for 30 minutes. After removing excess staining dye and air-drying, the samples were examined using a Carl Zeiss LSM 700 Laser Scanning Microscope with ZEN 2009 imaging software (Carl Zeiss, Germany). The coverage rate of bacteria on the surface was analysed using open source Image J 1.44 software (National Institute of Health, US).
  • Figure 5 A shows the titration effect on biofilm formation wherein Fe- Lac at 50, 100, and 300 mM inhibits the formation of biofilm by
  • Figure 5B shows the dispersion effect on biofilm formation wherein Fe-Lac at 10, 50, and 100 pM inhibits the formation of biofilm by
  • Example 3 Fe-Cit Prevention of biofilm formation by Pseudomonas aeruginosa.
  • the slides were removed from bacterial culture and washed with 15 mL phosphate buffered saline at room temperature for 5 minutes three times and then rinsed with distilled H 2 0. After washing, the slides were stained with 20 pM SYT017 dye (Invitrogen, UK) at room temperature for 30 minutes. After removing excess staining dye and air-drying, the samples were examined using a Carl Zeiss LSM 700 Laser Scanning Microscope with ZEN 2009 imaging software (Carl Zeiss, Germany). The coverage rate of bacteria on the surface was analysed using open source Image J 1.44 software (National Institute of Health, US). Results
  • Figure 6 shows the effect on biofilm formation wherein Fe-Cit at 100 and 300 mM inhibits the formation of biofilm by Pseudomonas aeruginosa. In the absence of Fe-Cit (control), a higher coverage rate was measured for Pseudomonas aeruginosa than in the presence of Fe-Cit.
  • Example 4 Fe-Tart Prevention of biofilm formation by Pseudomonas aeruginosa.
  • the slides were removed from bacterial culture and washed with 15 mL phosphate buffered saline at room temperature for 5 minutes three times and then rinsed with distilled FLO. After washing, the slides were stained with 20 mM SYT017 dye (Invitrogen, UK) at room temperature for 30 minutes. After removing excess staining dye and air-drying, the samples were examined using a Carl Zeiss LSM 700 Laser Scanning Microscope with ZEN 2009 imaging software (Carl Zeiss, Germany). The coverage rate of bacteria on the surface was analysed using open source Image J 1.44 software (National Institute of Health, US).
  • Figure 7 shows the effect on biofilm formation wherein Fe-Tart at
  • Pseudomonas aeruginosa PAO-l strain was routinely grown on either LB (Luria-Bertani, Oxoid, UK) agar plates at 37°C or in broth at 37°C with 200 rpm shaking.
  • the slides were removed from bacterial culture and washed with 15 mL phosphate buffered saline at room temperature for 5 minutes three times and then rinsed with distilled FLO.
  • FIG. 8 shows the effect on biofilm formation wherein Fe-Gly at
  • Example 7 Enhancement of weight gain in weanling pigs by administration of water soluble Fe-complexes
  • the objective of this pilot study is to evaluate the effect of three water soluble Fe-complexes (ferric lactate, ferric citrate and ferric tartrate) on growth performance and colonic microbiota of weaner pigs.
  • Treatment 1 were control diets, whilst Treatment 2 to 4 were through providing water that includes different Fe-complexes (Table 14).
  • the feeds used were standard commercial, non- medicated feeds, tailored for weaner pigs.
  • the feeds were offered as a 3 mm pellet and ad libitum. Water will also be available ad libitum.

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Abstract

L'invention concerne un procédé d'amélioration de la croissance d'un animal, ainsi que de traitement ou de prévention d'infections antimicrobiennes. Le procédé comprend les étapes consistant à faire ingérer ou absorber par l'animal une quantité efficace d'au moins un composé complexe Fe III, notamment mais non exclusivement, des complexes Fe III comportant des ligands liés à l'entité centrale fer, tels que des acides aminés ou des acides α-hydroxy. L'invention concerne également des procédés utiles dans l'inhibition, la réduction ou la prévention de la formation ou constitution d'un biofilm sur une surface ; le traitement, l'inhibition de croissance de bactéries et l'inhibition de la colonisation par des bactéries à la fois dans des environnements biologiques et non biologiques ; la désinfection de surfaces, la potentialisation des effets des antibiotiques et autres agents antimicrobiens, et l'augmentation de la sensibilité des bactéries et autres micro-organismes à des agents antimicrobiens.
EP19702139.7A 2018-01-03 2019-01-03 Compositions d'inhibition de biofilm destinées à l'amélioration de prise de poids du bétail Withdrawn EP3735128A1 (fr)

Applications Claiming Priority (2)

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US15/860,989 US10653658B2 (en) 2015-08-11 2018-01-03 Biofilm inhibiting compositions enhancing weight gain in livestock
PCT/US2019/012184 WO2019136150A1 (fr) 2016-02-17 2019-01-03 Compositions d'inhibition de biofilm destinées à l'amélioration de prise de poids du bétail

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