WO2019189331A1 - Nouvelle substance k95-5901-1 et procédé de production associé - Google Patents

Nouvelle substance k95-5901-1 et procédé de production associé Download PDF

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Publication number
WO2019189331A1
WO2019189331A1 PCT/JP2019/013132 JP2019013132W WO2019189331A1 WO 2019189331 A1 WO2019189331 A1 WO 2019189331A1 JP 2019013132 W JP2019013132 W JP 2019013132W WO 2019189331 A1 WO2019189331 A1 WO 2019189331A1
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WO
WIPO (PCT)
Prior art keywords
substance
tuberculosis
compound
actinoplanes
microorganism
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.)
Ceased
Application number
PCT/JP2019/013132
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English (en)
Japanese (ja)
Inventor
大村　智
塩見　和朗
美穂子 森
厚子 松本
定彦 鈴木
千絵 中島
山口　智之
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.)
Hokkaido University NUC
Kitasato Institute
Original Assignee
Hokkaido University NUC
Kitasato Institute
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Publication date
Application filed by Hokkaido University NUC, Kitasato Institute filed Critical Hokkaido University NUC
Priority to JP2020509177A priority Critical patent/JPWO2019189331A1/ja
Publication of WO2019189331A1 publication Critical patent/WO2019189331A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor

Definitions

  • the present invention relates to the field of compounds having the activity of inhibiting the growth of Mycobacterium tuberculosis, and pharmaceuticals and veterinary drugs containing the compounds.
  • Tuberculosis that is designated as a type 2 infectious disease is one of the three major infectious diseases, and as a single infectious disease, it is the second most common death in the world after HIV / AIDS. It is reported that there are 10.4 million tuberculosis patients, and 1.7 million people die from tuberculosis annually (2016, WHO). In HIV-infected persons, tuberculosis accounts for one-fifth of the cause of death.
  • rifampicin, isoniazid, pyrazinamide, streptomycin, ethambutol are used as the first-line drug, and levofloxacin, kanamycin, etionamide, enviomycin, paraaminosalicylic acid, cycloserine are used as the second-line drug, Used in combination of 3 or more agents.
  • multi-drug resistant tuberculosis resistant to these therapeutic agents has been spreading.
  • the emergence of multi-drug resistant tuberculosis and super multi-drug resistant tuberculosis, in which existing anti-tuberculosis drugs have no effect, has been seen in more than half of the world, and these measures are an urgent issue in the international community.
  • Non-patent Document 1 Cyclomarine, a kind of Clp protease disruptor, is a Streptomyces sp. Is a heptapeptide obtained from Cyclomarin acts on the ClpC1 subunit of Mycobacterium tuberculosis Clp, causing its function to run away and inducing cell death.
  • Iramycin is a deep-sea derived Streptomyces atratus It is an analog of cyclomarin isolated from SCSIO ZH16 and is also considered to be a Clp protease disruptor.
  • iramycin C is a compound represented by the following structure, but it has been reported that the activity of this compound against Mycobacterium tuberculosis H37Rv is as low as 9.6 ⁇ M ( Non-patent document 2).
  • the production method according to 3. (5) A microorganism belonging to actinomycetes and capable of producing the substance K95-5901-1. (6) Actinoplanes sp. K95-5901 (Accession No. NITE BP-02658) strain. (7) A pharmaceutical composition comprising the compound according to (1) or a salt thereof, or a hydrate or solvate thereof as an active ingredient. (8) The pharmaceutical composition according to (7), which is an antituberculosis drug. (9) The pharmaceutical composition according to (8), which is a tuberculosis growth inhibitor.
  • the substance K95-5901-1 of the present invention has tuberculosis growth inhibitory activity. Therefore, according to the present invention, the K95-5901-1 substance can be effectively used as a therapeutic or prophylactic agent for tuberculosis.
  • the K95-5901-1 substance is a compound represented by the following formula (I).
  • the salt of the substance K95-5901-1 is a salt formed by combining the substance K95-5901-1 with an inorganic or organic base or acid.
  • the salt include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N -Salts of amines such as bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine; or bases such as lysine, ⁇ -hydroxylysine, arginine And a salt with a functional amino acid.
  • alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium
  • ammonia methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane,
  • hydrates and solvates of the K95-5901-1 substance and hydrates and solvates of the salt of the K95-5901-1 substance are also encompassed by the compounds of the present invention.
  • the K95-5901-1 substance or the compound represented by the formula (I) is a salt of the K95-5901-1 substance even when it is not specified unless it is clearly not suitable. Hydrates and solvates as well as hydrates or solvates of the salts of the compound K95-5901-1 substance.
  • the compound of the present invention may have an asymmetric carbon, optical isomers may exist.
  • the compound of the present invention may be either a dextrorotatory (+) or levorotatory ( ⁇ ) compound, or a mixture of these isomers such as a racemate.
  • the compound of the present invention includes any tautomer or geometric isomer (for example, E-form, Z-form, etc.).
  • the K95-5901-1 substance of the present invention can be obtained by culturing a microorganism capable of producing the K95-5901-1 substance belonging to actinomycetes, and separating and purifying it from the culture.
  • Actinomycetes that can be used for the production of the K95-5901-1 substance of the present invention include actinoplanes sp. Actinoplanes sp. K95-5901 (Accession number NITE BP-02658) and its mutant strains. All of the K95-5901-1 substance-producing bacteria belonging to the fungus (preferably belonging to the genus Actinoplanes).
  • the nutrient source in actinomycetes culture suitable for the production of the above K95-5901-1 substance is not particularly limited and can be used as a nutrient source for actinomycetes.
  • a nutrient source for actinomycetes for example, commercially available peptone, meat extract, corn steep liquor, cottonseed flour, peanut flour, soy flour, yeast extract, NZ-amine, casein hydrate, nitrogen sources such as sodium nitrate, ammonium nitrate, ammonium sulfate, glycerin
  • carbohydrates such as starch, glucose, galactose and mannose, or carbon sources such as fat
  • inorganic salts such as sodium chloride, phosphate, calcium carbonate and magnesium sulfate can be used alone or in combination.
  • a trace amount of metal salt and animal / plant / mineral oil as an antifoaming agent may be added to the medium for actinomycete culture if necessary.
  • These additives may be any additives that can be used to produce the K95-5901-1 substance using the production bacteria, and all known actinomycete culture materials can be used.
  • the culture temperature of actinomycete culture can be applied in any range in which the producing bacteria can grow and produce the K95-5901-1 substance. Culturing can be carried out by appropriately selecting according to the properties of the K95-5901-1 substance-producing bacterium using the conditions described above.
  • the K95-5901-1 substance can be extracted from the culture solution with a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • known methods used for collecting fat-soluble substances such as adsorption chromatography, partition chromatography, gel filtration chromatography, scraping from thin layer chromatography, centrifugal countercurrent distribution chromatography, high speed It can be purely collected by appropriately combining or repeating liquid chromatography and the like.
  • the present invention also relates to a pharmaceutical composition containing the substance K95-5901-1, particularly an antituberculous drug.
  • the invention relates to the use of the K95-5901-1 substance for the manufacture of an antituberculosis drug.
  • the present invention relates to the K95-5901-1 substance for treating or preventing tuberculosis.
  • the present invention further relates to a method for treating and preventing tuberculosis comprising administering an effective amount of a K95-5901-1 substance to a patient in need thereof.
  • the pharmaceutical composition of the present invention can be used as a therapeutic or prophylactic agent for tuberculosis.
  • the pharmaceutical composition of the present invention comprises drug-resistant tuberculosis bacteria in which existing drugs are not effective, multi-drug resistant tuberculosis bacteria having resistance to a plurality of drugs, and super multi-drugs that are resistant to all existing drugs. It can be used as a therapeutic or prophylactic agent for infection with resistant M. tuberculosis.
  • the tuberculosis bacterium to be treated and prevented according to the present invention is a resistant bacterium
  • the tuberculosis bacterium is selected from rifampicin, isoniazid, pyrazinamide, streptomycin, ethambutol, levofloxacin, kanamycin, etionamide, enbiomycin, paraaminosalicylic acid, and cycloserine.
  • Resistant to at least one selected drug and may be resistant to any type of drug between two or more and all types.
  • the M. tuberculosis subject to treatment and prevention of the present invention may be resistant to rifampicin and isoniazid.
  • the pharmaceutical composition of the present invention may be a combination of K95-5901-1 substance and one or more other antituberculous drugs.
  • the other antituberculosis drugs include rifampicin, isoniazid, pyrazinamide, streptomycin, ethambutol, levofloxacin, kanamycin, ethionamide, enbiomycin, paraaminosalicylic acid, and cycloserine.
  • These concomitant drugs may be provided as a single preparation, or may be provided as separate preparations for use in combination (for example, kits).
  • the pharmaceutical composition of the present invention can be used for oral administration or parenteral administration.
  • the dosage form of the pharmaceutical composition includes topical preparations, suspensions, ointments, creams, gels, inhalants, injections (for example, intravenous injections, subcutaneous injections, intramuscular injections). , Infusion), tablets, capsules, tablets, granules, powders, and the like.
  • the pharmaceutical composition of the present invention can be formulated by a conventional method using a normal pharmaceutically acceptable carrier.
  • a pharmaceutical composition containing the K95-5901-1 substance as an active ingredient and solid preparations such as tablets, pills, capsules, powders, granules, solutions, suspensions, It can be used orally as a liquid preparation such as an emulsion, or parenterally as an injection, intravenous, intramuscular, subcutaneous, or the like, a suppository, or a patch.
  • a solid preparation for oral administration When preparing a solid preparation for oral administration, add excipients to the active ingredient and, if necessary, binders, disintegrants, lubricants, etc., and then add solvents, granules, powders, capsules, etc. by conventional methods. And When preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizing agent, etc. may be added to the main drug as necessary to obtain a subcutaneous or intravenous injection by a conventional method.
  • the present invention can further be used in a method of treating or preventing M. tuberculosis infection comprising administering an effective amount of K95-5901-1 substance to a patient in need thereof.
  • a pharmaceutical composition containing the K95-5901-1 substance as an active ingredient is administered orally or parenterally such as an injection or infusion. It can be administered in the form.
  • the K95-5901-1 substance is administered to mammals, it may be administered orally as tablets, powders, granules, syrups, etc., or parenterally as injections or drops.
  • the dose varies depending on symptoms, age, sex, body weight, dosage form, etc. For example, when administered orally to an adult, the daily dose is usually 0.1-1000 mg.
  • Example 1 Mycological characteristics of Actinoplanes sp. K95-5901 strain Actinoplanes sp. K95-5901 (Accession number NITE BP-02658) strain was collected in Asaka, Saitama, Japan. This strain is isolated from soil and its mycological properties are as follows. (I) Morphological properties Vegetative mycelium develops well on various agar media, and no fragmentation is observed. The aerial mycelium does not settle, but forms a spherical spore capsule of about 5 to 10 ⁇ m on the vegetative mycelium.
  • Diaminopimelic acid in the cell wall is meso-type.
  • Major menaquinone has a small amount of MK-8 in MK-9 (H 4) ( H 4) and MK-10 (H 4).
  • Example 2 Isolation and extraction, physicochemical properties, and structure of substance K95-5901-1 From Actinoplanes sp. K95-5901 (Accession No. NITE BP-02658) strain cultured in an agar slant medium , Starch 2.4%, glucose 0.1%, peptone 0.3%, meat extract 0.3%, yeast extract (produced by Oriental Yeast Co., Ltd.) 0.5%, calcium carbonate 0.4%
  • One platinum loop was inoculated into a test tube containing 10 ml of a liquid medium (pH 7.0) and cultured with shaking at 27 ° C. for 3 days.
  • the obtained seed culture solution was soluble starch 2.0%, glycerol 0.5%, wheat germ 1.0%, meat extract 0.3%, dry yeast (Fermipan, DSM Bakery Ingredients). 1 ml each was inoculated into 30 500 ml Erlenmeyer flasks containing 100 ml of a liquid medium (pH 7.5) consisting of 3% and calcium carbonate 0.3%, and cultured with shaking at 25 ° C. for 6 days.
  • a liquid medium pH 7.5
  • the K95-5901-1 substance has a structure represented by the following formula (I).
  • Example 3 Antibacterial activity of K95-5901-1 substance against Mycobacterium spp.
  • multidrug resistant (rifampicin and isoniazid resistant) clinically isolated Mycobacterium tuberculosis W-26 strain and W-114 strain was used.
  • Bacterial colonies within 8 weeks grown on Ogawa medium were suspended in mycobroth [manufactured by Kyokuto Pharmaceutical Co., Ltd.] and culture was started at 37 ° C. The culture solution was stirred every day, and turbidity was measured at a wavelength of 530 nm using a digital colorimeter Vi-spec II (manufactured by Kyokuto Pharmaceutical Co., Ltd.), and the culture was continued until the turbidity reached 0.15.
  • the antibacterial activity of the K95-5901-1 substance of the present invention against test bacteria other than the genus Mycobacterium is as follows. 10 ⁇ l each of a 1 mg / ml methanol solution of the K95-5901-1 substance was immersed in a filter paper disc (Advantech Toyo Co., Ltd., diameter 6 mm), air-dried for a certain period of time, and the solvent was removed. Attached to agar plates each containing the test bacteria and cultured at 35 ° C. for 24 hours, the diameter of the growth inhibition circle formed around the filter paper disc was measured.
  • the results are shown in Table 3.
  • the K95-5901-1 substance of the present invention showed no antibacterial activity against bacteria and fungi other than Mycobacterium smegmatis, Bacillus subtilis and Micrococcus luteus among the microorganisms shown in Table 3. Therefore, the K95-5901-1 substance of the present invention can be used as a drug such as an antituberculosis drug exhibiting antibacterial activity against Mycobacterium.

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Abstract

La présente invention se rapporte à la recherche d'une substance antibiotique efficace pour Mycobacterium tuberculosis résistant aux médicaments multiples dans une solution de culture de micro-organismes.La présente invention concerne une nouvelle substance K95-5901-1 ayant la structure suivante, dans des produits d'actinobacterium, actinoplanes sp. K95-5901.Cette substance exprime une activité d'inhibition de la prolifération de Mycobacterium tuberculosis résistant aux médicaments à une concentration inférieure à un niveau de micromole, et qui présente une cytotoxicité très faible. Par conséquent, la présente invention concerne une nouvelle substance ayant une activité d'inhibition de la prolifération de Mycobacterium tuberculosis.
PCT/JP2019/013132 2018-03-28 2019-03-27 Nouvelle substance k95-5901-1 et procédé de production associé Ceased WO2019189331A1 (fr)

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JP2020509177A JPWO2019189331A1 (ja) 2018-03-28 2019-03-27 新規ｋ９５−５９０１−１物質およびその製造方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4089103A1 (fr) * 2021-05-12 2022-11-16 Universität Duisburg-Essen Heptapeptides cycliques de liaison protéase clpcp

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078797A1 (fr) * 1999-06-21 2000-12-28 Eli Lilly And Company Derives de rufomycine presentant une grande utilite comme antibiotiques
JP2014512380A (ja) * 2011-04-18 2014-05-22 ミョンジ ユニヴァーシティ インダストリー アンド アカデミア コーペレーション ファウンデーション ノノムラエ種からの環状ペプチド、その生産プロセス、およびそれを含むマイコバクテリア関連疾病の治療または予防のための薬学的組成物
CN106279370A (zh) * 2016-09-06 2017-01-04 中国科学院南海海洋研究所 一种海洋链霉菌、及其环肽化合物在制备抗结核分枝杆菌药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078797A1 (fr) * 1999-06-21 2000-12-28 Eli Lilly And Company Derives de rufomycine presentant une grande utilite comme antibiotiques
JP2014512380A (ja) * 2011-04-18 2014-05-22 ミョンジ ユニヴァーシティ インダストリー アンド アカデミア コーペレーション ファウンデーション ノノムラエ種からの環状ペプチド、その生産プロセス、およびそれを含むマイコバクテリア関連疾病の治療または予防のための薬学的組成物
CN106279370A (zh) * 2016-09-06 2017-01-04 中国科学院南海海洋研究所 一种海洋链霉菌、及其环肽化合物在制备抗结核分枝杆菌药物中的应用

Non-Patent Citations (4)

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Title
BARBIE, P. ET AL.: "Total synthesis of cyclomarins A, C and D, marine cyclic peptides with interesting anti-tuberculosis and anti-malaria activities", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 14, no. 25, 2016, pages 6036 - 6054, XP055639186 *
INTARAUDOM, C. ET AL.: "Antimalarial and antituberculosis substances from Streptomyces sp. BCC26924", TETRAHEDRON, vol. 67, no. 39, 2011, pages 7593 - 7597, XP028277225, doi:10.1016/j.tet.2011.07.053 *
SCHMITT, E. K . ET AL.: "The Natural Product Cyclomarin Kills Mycobacterium Tuberculosis by Targeting the ClpCl Subunit of the Caseinolytic Protease", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 50, no. 26, 11 May 2011 (2011-05-11), pages 5889 - 5891, XP055639184 *
ZHAO, P. ET AL.: "Actinobacteria-Derived peptide antibiotics since 2000", PEPTIDES, vol. 103, 19 March 2018 (2018-03-19), pages 48 - 59, XP055639191 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4089103A1 (fr) * 2021-05-12 2022-11-16 Universität Duisburg-Essen Heptapeptides cycliques de liaison protéase clpcp

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