WO2016080665A1 - Procédé de production de daptomycine à l'aide de glycérides décanoyles - Google Patents

Procédé de production de daptomycine à l'aide de glycérides décanoyles Download PDF

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WO2016080665A1
WO2016080665A1 PCT/KR2015/011231 KR2015011231W WO2016080665A1 WO 2016080665 A1 WO2016080665 A1 WO 2016080665A1 KR 2015011231 W KR2015011231 W KR 2015011231W WO 2016080665 A1 WO2016080665 A1 WO 2016080665A1
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daptomycin
decanoyl
streptomyces
decanoic acid
present
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서정우
김병국
서민정
이경민
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CKD Bio Corp
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/04—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using bacteria
    • 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
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/82—Proteins from microorganisms
    • Y10S530/825—Bacteria

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  • the present invention was made by the task number PJ009541 under the support of the Rural Development Administration, the research and management agency of the project is the Rural Development Administration, the research project name is "next generation Biogreen 21 project”, the research title is "industrial production of actinomycetes-derived Lipopeptide antibiotics Technology development ”, the host institution is Chong Kun Dang Bio Co., Ltd. and the research period is 2013.2.1 ⁇ 2014.12.31.
  • the present invention relates to a method for producing daptomycin using decanoyl glycerides.
  • Dapto azithromycin is an effective antibiotic in the Gram-positive, including the methicillin-resistant Staphylococcus aureus (methicillin- resistant Staphylococcus aureus, MRSA) and vancomycin-resistant Enterococcus Kokai (vancomycin-resistant Enterococci, VRE) pathogens (Clinical Infections Diseases, 38 : P. 1673-1681, 2004).
  • daptomycin was approved by the US Food and Drug Administration (FDA) in 2003 under the name Cubicin ® , Cubist Pharmaceuticals, for the treatment of skin infections or skin tissue infections caused by Gram-positive pathogens.
  • Streptomyces roseosporus is a secondary metabolite that produces a variety of A21978C derivatives in the form of circular lipopeptides consisting of 13 amino acids and one fatty acid ( The Journal of Antibiotics , 40: P.761-777, 1987).
  • A21978C derivatives the structure in which decanoic acid is bound to the fatty acid binding site is daptomycin, which has excellent biological activity ( The Journal of Antibiotics , 40: P.761-777, 1987).
  • the industrial manufacturing process of daptomycin is divided into semisynthetic method by enzyme and fermentation method by addition of decanoic acid.
  • Enzymatic semisynthesis involves the first step in producing A21978C from Streptomyces roseosporus; Actinoplanes utahensis ) second step of deacylation (deacylation) reaction using an enzyme; And a third step of attaching n-decanoyl groups synthetically (US Pat. No. 382,012, Journal of Antibiotics , 41: P.1093-1105, 1988).
  • the preparation of daptomycin by the semi-synthetic method is very complicated and the economic cost is high due to the high manufacturing cost.
  • the main impurities produced after daptomycin fermentation are derivatives lacking some of the amino acids in the daptomycin structure, derivatives lacking or adding one methyl group to the decanoic acid structure, oxidative analogues, beta At least 13 different derivatives are known, including isomers, ⁇ -isomers, anhydro-daptomycins and lactone hydrolysis products (European Patent No. 1,252,179 B1).
  • Multi-step purification process such as anion exchange chromatography, hydrophobic interaction chromatography and anion exchange chromatography, modified buffer enhanced anion exchange chromatography to remove various derivatives in the culture and produce high purity daptomycin (European Patent No. 1,252,179 B1).
  • the yield is reduced and expensive resins are required due to the large number of derivatives present in the culture of daptomycin produced using decanoic acid or coupe oil as precursors. have.
  • the fermentation method is preferable to the semisynthetic method by enzymes, and in this case, it is urgently needed to develop a fermentation process in which the productivity of daptomycin is improved and the flexible material is reduced.
  • Another object of the present invention is to provide daptomycin produced by the method of the present invention.
  • Still another object of the present invention is to provide a composition for preparing daptomycin.
  • the present invention provides a method for producing daptomycin comprising the following steps.
  • the present inventors have a problem that the bacterium is soluble due to the toxicity of decanoic acid, which is added as a precursor during fermentation of daptomycin using microorganisms of Streptomyces, and has a limitation in increasing productivity due to the addition of high concentration and decanoic acid. Efforts have been made to reduce the large amounts of daptomycin derivatives produced at the time. As a result, when decanoyl glyceride is added as a precursor of n-decanoyl side chain of daptomycin and used as a precursor, there is no problem of inhibiting cell growth when adding decanoic acid directly, and the productivity of daptomycin is markedly increased. It was found that the derivative of daptomycin, which is a causative agent of significantly lowering the yield, was reduced in the separation and recovery of daptomycin.
  • the most important feature of the present invention is the use of decanoyl glycerides as precursors for daptomycin fermentation.
  • the decanoyl glyceride used as a precursor in daptomycin fermentation in the present invention is decanoyl monoglyceride, decanoyl diglyceride or decanoyl triglyceride.
  • the decanoyl glyceride used as precursor in the daptomycin fermentation in the present invention is decanoyl triglyceride.
  • the decanoyl triglyceride used in the present invention is mostly composed of decanoic acid, and through this feature, it is very unlikely to generate a flexible substance during daptomycin fermentation compared to other precursors containing various fatty acids in addition to decanoic acid.
  • the strain used for the production of daptomycin in the present invention is a strain of the genus Streptomyces.
  • Streptomyces sp. Strains used in the present invention are Streptomyces coelicolor ( S. coelicolor ), Streptomyces lividans ( S. lividans ), Streptomyces albican ( S . albicans), Streptomyces draw three-house (S. griseus), Streptomyces Philippe Kato sports Russ (S. plicatosporus), Streptomyces sub rutile Russ (S. subrutilus), Streptomyces star right cephalosporin (S. staurosporine ), S. scabiei or S. ipomoeae , Streptomyces roseosporus .
  • the strain Streptomyces sp. Used in the present invention is a CKDBD 1100 strain (KCTC 12558BP) of Streptomyces genus having a 16S rRNA sequence of SEQ ID NO: 1.
  • the media components and the amount of addition used for the production of daptomycin can be determined by those skilled in the art with reference to various methods known in the art.
  • the culture pH for culturing daptomycin using the strain Streptomyces sp is preferably pH 5-8, more preferably pH 5.5-7.5, even more Preferably pH 6.0-7.0.
  • Culture temperature conditions for daptomycin fermentation are 25-35 ° C. and preferably 28-32 ° C.
  • Dissolved oxygen conditions for daptomycin fermentation are 20-80%, preferably 30-70% and more preferably 40-60%.
  • Stirring conditions for daptomycin fermentation are 100-500 rpm, preferably 100-400 rpm and more preferably 100-300 rpm.
  • Culture conditions for the production of daptomycin can be determined by experimentation by those skilled in the art according to various methods or strains known in the art, medium composition, culture scale and other considerations.
  • decanoyl glycerides added for the production of daptomycin are added at a concentration of 1 ml to 100 ml per 1 L of culture, more preferably 20 ml to 80 ml per 1 L of culture, Even more preferably 40 ml to 70 ml per liter of culture.
  • the addition rate of decanoyl glycerides added for daptomycin production is 0.1 ml / L hours to 3.0 ml / L hours, more preferably 0.1 ml / L hours to 2.0 ml / L hour, even more preferably 0.5 ml / L hour to 1.5 ml / L hour.
  • 0.1-10 g of daptomycin can be produced per 1 L of strain culture by the method of the present invention.
  • the use of the production method of the present invention can reduce the flexible material compared to the method for producing daptomycin using decanoic acid (decanoic acid) as a precursor.
  • flexible material refers to impurities (starting materials, intermediates, by-products, decomposition products, etc.) that may be produced in the production of daptomycin.
  • the strain culture medium of Streptomyces genus can be centrifuged to separate the culture medium and the strain, and then daptomycin can be extracted by adding a suitable extraction solvent to the culture medium supernatant.
  • methanol is added to a strain culture of Streptomyces spp, followed by microfiltration and concentration under reduced pressure to obtain daptomycin.
  • methanol is added to the strain culture of Streptomyces sp. Microfiltration and concentrated under reduced pressure, followed by chromatography to obtain daptomycin.
  • the method of the present invention described above can produce daptomycin in higher purification yield and purity compared to the method for producing daptomycin using decanoic acid and coupe oil.
  • the present invention provides daptomycin produced by the method of the present invention.
  • the present invention provides a composition for preparing daptomycin comprising Streptomyces sp. CKDBD 1100 strain comprising decanoyl glyceride.
  • the present invention provides a method for producing daptomycin comprising the step of culturing by adding decanoyl glyceride as a material of n-decanoyl side chain to the culture medium of the strain of Streptomyces sp.
  • the method for producing daptomycin according to the present invention does not have a problem of inhibiting cell growth caused by adding decanoic acid directly because decanoyl glyceride is added as a material of n-decanoyl side chain.
  • the method for producing daptomycin according to the present invention enables the addition of decanoyl glycerides at a high concentration as a material of the n-decanoyl side chain, thereby showing a markedly increased daptomycin productivity.
  • the present invention provides a composition for preparing daptomycin comprising daptomycin and Streptomyces CKDBD 1100 strain (KCTC 12558BP) and decanoyl glyceride produced by the method of the present invention.
  • the method of the present invention significantly increases daptomycin productivity by using decanoyl glycerides as precursors in daptomycin fermentation, compared to using decanoic acid or natural oils containing a large number of impurities in addition to decanoic acid, Significantly reduced softeners have greatly simplified the purification process and enabled the production of high purity daptomycin with improved yields.
  • FIG 1 shows the structure of daptomycin.
  • Figure 2 shows the structure of decanoic acid and decanoyl triglycerides.
  • Figure 3 shows the results of microscopic observation of a sample of the fermentation broth CKDBD 1100 strain (KCTC 12558BP) fermented with decanoic acid and decanoyl triglyceride, respectively in a fermentor. This shows that the growth inhibition for the strain is small when the decanoyl triglyceride addition.
  • Figure 4 shows the results of analysis of the extract of the fermentation broth CKDBD 1100 strain (KCTC 12558BP) in the fermentation broth with the addition of decanoic acid and decanoyl triglyceride, respectively, by high performance liquid chromatography. This shows an increase in productivity and a decrease in softeners when decanoyl triglyceride is added.
  • Glycerol solution the genus Streptomyces stored in cryogenic freezer of -70 °C (Streptomyces sp .) CKDBD 1100 strain (KCTC 12558BP) was prepared, and then inoculated into a test tube in which 5 mL of the seed medium (DS medium) was added thereto, followed by vibrating culture at 28-32 ° C. and 220 rpm for 20-30 hours.
  • the culture medium of the DS medium was added to a 100 mL Erlenmeyer flask added with 20 mL of production medium (DM medium) shown in Table 2 and having a decanoic acid concentration of 0, 5, 10, 15, 20, 25, 30 mL / L. 1 mL each was inoculated and vibrated at 220 rpm at 28-32 ° C. for 5 days.
  • Daptomycin productivity and bacterial growth according to the concentration of decanoic acid was as shown in Table 3.
  • the productivity of daptomycin was 5.6 mg / L without the addition of decanoic acid, but the productivity of daptomycin increased with increasing concentrations, resulting in 22.5 mg / L of daptomycin productivity after 15 mL / L.
  • 30 mL / L of decanoic acid was added, no daptomycin was produced.
  • Seed medium used to culture daptomycin producing bacteria (DS medium) ingredient Concentration (g / L) Soy flour 25 Dextrose 25 SAG-471 0.5
  • DM medium Production medium used for culturing daptomycin producing bacteria
  • DM medium ingredient Concentration (g / L) dextrin 60 Dextrose 10 Soy flour 20 Calcium carbonate One Oxalic acid 2 SAG-471 0.5
  • Example 1 As the concentration of decanoic acid, which is a precursor of daptomycin, is increased in the production medium, the inhibition of the growth of bacteria is severe, and thus it may be confirmed that there is a limit in increasing the productivity of daptomycin.
  • CKDBD 1100 strain (KCTC 12558BP) was inoculated in a test tube to which 5 mL of the seed medium (DS medium) of Table 1 was incubated at 28-32 ° C. and 220 rpm for 20-30 hours.
  • the culture medium of the DS medium was added to 20 mL of production medium (DM medium) and 100 mL of triangulum added so that decanal, soybean oil, palm seed oil, coconut oil, coupe oil, and decanoyl triglyceride were 15 mL / L, respectively.
  • DM medium production medium
  • 1 mL each of the flask was inoculated and vibrated at 220 rpm at 28-32 ° C. for 5 days.
  • Table 4 shows the productivity, cell weight and viscosity of daptomycin according to the type of precursor added.
  • the productivity of daptomycin was 22.5 mg / L with decanoic acid but increased to 64.3 mg / L with decanal and decanoyl triglyceride, respectively.
  • decanoyl triglyceride daptomycin showed the highest productivity of 380 mg / L, followed by coupe oil, coconut oil, palm seed oil, and soybean oil.
  • the cell mass was 23-26% and the viscosity was 136-183 cP, showing good growth.
  • the cell mass and viscosity were significantly low, indicating that the growth of bacteria was greatly reduced.
  • Daptomycin Productivity and Bacteria Growth by Precursor Type Precursor type Daptomycin (mg / L) Growth of bacteria Cell weight (%) Viscosity (cP) No addition 5.6 24 145 Decanoic acid 22.5 16 34 Decanal 64.3 18 72 Soybean oil 6.4 26 183 Palm seed oil 37.5 25 170 Coconut oil 49.2 23 136 Coupe oil 122 24 158 Synthetic decanoyltriglycerides 380 25 163
  • Example 2 the fatty acid content contained in each of the oils used in the medium for daptomycin fermentation was analyzed.
  • the analytical principle is to treat the fats and oils with methanolic sodium hydroxide solution to make alkali salts, add trifluoroboranmethanol solution, and heat and esterify the resulting fatty acid esters in isooctane. Fatty acid content is analyzed.
  • GC-FID gas chromatography-flame ionization detector
  • decanoic acid a precursor of daptomycin
  • decanoic acid C10: 0
  • decanoic acid C10: 0
  • decanoic acid C10: 0
  • decanoyl triglyceride has 0.1% caprylic acid (C8: 0), which contains almost no fatty acids other than decanoic acid, but 6-8 kinds of fatty acids other than decanoic acid in soybean oil, palm oil, coconut oil, and coupe oil. It can be seen that the above exists. Therefore, when the oils containing a lot of fatty acids other than decanoic acid are used as precursors for daptomycin fermentation, it is very likely that a large amount of flexible substances are produced and productivity is reduced.
  • Example 4 Decanoil Triglycerides According to concentration Daptomycin Productivity and Germ Growth
  • Example 3 From Example 3, it was necessary to investigate the effect of the addition concentration of decanoyl triglyceride which showed excellent growth of bacteria and the highest daptomycin productivity among the precursors of daptomycin added to the production medium.
  • DS medium seed medium
  • the culture medium of the DS medium was added to a 100 mL Erlenmeyer flask, where 20 mL of production medium (DM medium) was added and decanoyl triglyceride was added to 0, 10, 20, 30, 40, 50, and 60 mL / L, respectively. 1 mL each was inoculated and vibrated at 220 rpm at 28-32 ° C. for 5 days.
  • DM medium production medium
  • Daptomycin productivity and bacterial growth according to decanoyl triglyceride addition concentration are shown in Table 5.
  • the productivity of daptomycin is 5.6 mg / L without the addition of precursors, but the productivity of daptomycin is significantly increased as the concentration of decanoyl triglyceride is increased, resulting in maximum productivity of 560 mg / L when 50 mL / L is added. .
  • Daptomycin Productivity and Bacteria Growth with Decanoyl Triglyceride Concentration Decanoyltriglyceride (mL / L) Daptomycin (mg / L) Growth of bacteria PMV (%) Viscosity (cP) 0 5.6 24 145 10 160 25 156 20 290 25 175 30 380 26 173 40 470 28 188 50 560 28 209 60 520 27 240
  • the rate of addition of decanoic acid solution in the fermenter is strictly controlled so as to maximize daptomycin productivity within the range that minimizes the growth inhibition against the bacteria due to the inhibition of growth of bacteria by decanoic acid. Should be.
  • the culture composition of the seed culture, the preculture and the main culture described in the above-mentioned means were solved. Seed culture was incubated in a 500 mL Erlenmeyer flask at a volume of 50 mL, and the culture temperature was maintained at 28-32 ° C. and the stirring speed was 120 rpm, and cultured for 20-30 hours.
  • the preculture was incubated at a volume of 2 L in a 5 L fermenter, the initial stirring speed was 200 rpm, the culture temperature was maintained at 28-32 °C, dissolved oxygen 40-60% and incubated for 20-30 hours.
  • the main culture was incubated in a 5 L fermenter at a volume of 2 L.
  • the initial stirring rate was 200 rpm, the culture temperature was 28-32 ° C., the dissolved oxygen content was 40-60%, and the pH was maintained at 6-7.
  • the decanoic acid solution was added at a rate of 0.1-1.0 mL / L hours from 20-30 hours after incubation, and the culture was performed for 10-13 days.
  • Daptomycin productivity and bacterial growth according to the addition rate of the decanoic acid solution was shown in Table 7 below.
  • the decanoic acid addition rate increases, it can be confirmed that the growth of the bacteria is greatly inhibited by the decanoic acid because the cell weight and viscosity decrease.
  • Example 6 in fermenter Coupe Effect of the rate of addition of the oil solution
  • Daptomycin productivity and bacterial growth according to the addition rate of the coupe oil solution are shown in Table 8 below.
  • the maximum productivity was 2,620 mg / L when the addition rate was 0.5 mL / L.h for the decanoic acid solution
  • the coupea oil addition rate was 1.0 mL / L.h.
  • Daptomycin Productivity and Bacteria Growth with Addition Rate of Coupea Oil Solution Addition rate (mL / L time) Daptomycin (mg / L) Growth of bacteria PMV (%) Viscosity (cP) 0.1 240 33 455 0.5 560 34 462 1.0 890 36 490 1.5 1050 34 473 2.0 930 35 468
  • the culture of the fermenter was carried out by applying the medium composition of the seed culture, the preculture and the main culture described in the solution of the above problem.
  • the addition rate of decanoyl triglyceride was 0.1-2.0 mL / L. Hours, and the other culture conditions such as culture temperature, aeration stirring, dissolved oxygen maintenance concentration, and pH maintenance were performed in the same manner as in Example 5.
  • Daptomycin productivity and bacterial growth according to the addition rate of decanoyl triglyceride solution was as shown in Table 9 below.
  • the maximum productivity was 2,620 mg / L when the addition rate of the decanoic acid solution was 0.5 mL / L.h, whereas 3,080 mg when the addition rate was 0.5 mL / L.h for the decanoyl triglyceride. It showed a productivity of / L and a maximum productivity of 4,770 mg / L when the addition rate was 1.5 mL / L. hours.
  • the growth of bacteria was increased until the addition rate of decanoyl triglyceride solution was 0.5 mL / L.
  • the mycelia In the medium added with decanoic acid, the mycelia were short, many nodes, and many mycelium pellet growth forms were observed. In the medium added with coupe oil or decanoyl triglyceride solution, the length of mycelia was long and node The mycelial growth form was the most common. Decanoic acid is highly toxic to the bacteria when added to grow in the form of agglomerates mycelium, and the access to nutrients and oxygen inside the pellet (pellet) can decrease the intracellular metabolic activity. As a result, the growth rate of the bacterium is slowed down or the cell lysis occurs, so that the addition of decanoic acid at a high concentration lowers daptomycin productivity.
  • decanoyl triglycerides are not toxic to bacteria on their own and can be used for the growth of bacteria and the synthesis of daptomycin as they grow slowly into glycerol and decanoic acid as they grow. It can be said to maintain mycelial growth form. As a result, even when decanoyl triglyceride is added at a higher concentration than decanoic acid, the growth of bacteria can be maintained and productivity can be seen to increase.
  • coupe oil like decanoyl triglyceride, has little inhibition on the growth of bacteria, but contains various fatty acids and other impurities as well as decanoic acid in monoglycerides, diglycerides and triglycerides, including free fatty acids. Daptomycin may not be high in productivity.
  • decanoyl triglyceride as a precursor in daptomycin fermentation, not only decanoic acid or natural oil containing a large number of impurities in addition to decanoic acid, but also significantly increased productivity and significantly reduced softening substances,
  • the mycin purification process is much simplified and yield improvement and high purity daptomycin production are possible.
  • Example 10 from culture Daptomycin refine
  • the purity and purification yield were higher than the culture solution to which the other precursor was added with a purity of 95.1% and a purification yield of 46.5% even though the reverse phase chromatography was performed twice.
  • decanoic acid-containing cultures increase cell debris and derivatives due to lysis of bacteria, and daptomycin derivatives due to other fatty acids and impurities contained in oils in coupe oil-containing cultures. Although a large amount is produced, the purification yield and the purity of the product are decreased, but when decanoyl triglyceride is added to the culture solution, not only the fermentation productivity is increased but also the purification yield and the purity of the product are greatly increased.
  • the deposit of the present strain was made by task number PJ009541 under the support of the Rural Development Administration of Korea.

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Abstract

La présente invention concerne un procédé qui permet de produire de la daptomycine et qui comprend une étape de culture par l'ajout, à un milieu de culture d'une souche de Streptomyces sp., de glycéride décanoyle en tant que matériau d'une chaîne latérale n-décanoyle. Le procédé de production de daptomycine de la présente invention ajoute un glycéride décanoyle, en tant que matériau d'une chaîne latérale n-décanoyle, et, ainsi, est exempt du problème d'inhibition de la croissance cellulaire microbienne qui apparaît lorsque l'acide décanoïque est ajouté directement. Le procédé de production de daptomycine de la présente invention peut ajouter un glycéride décanoyle, en tant que matériau d'une chaîne latérale n-décanoyle, en une concentration élevée, et présente ainsi une productivité de daptomycine considérablement augmentée. La présente invention concerne la daptomycine produite par le procédé de la présente invention et une composition pour la préparation de daptomycine comportant la souche de Streptomyces sp. CKDBD 1100 (KCTC 12558BP) et un glycéride décanoyle. Le procédé de la présente invention utilise un glycéride décanoyle en tant que précurseur dans la fermentation de la daptomycine, et augmente ainsi de manière significative la productivité de la daptomycine par rapport au cas dans lequel est utilisé de l'acide décanoïque ou une huile naturelle contenant de nombreuses impuretés autres que l'acide décanoïque ; ledit procédé simplifie en outre le procédé de purification par une réduction significative des substances associées et permet la production de daptomycine de grande pureté tout en améliorant le rendement.
PCT/KR2015/011231 2014-11-19 2015-10-22 Procédé de production de daptomycine à l'aide de glycérides décanoyles Ceased WO2016080665A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110642872A (zh) * 2019-11-18 2020-01-03 湖北宏中药业股份有限公司 一种星孢菌素提取方法
US20230118242A1 (en) * 2019-07-01 2023-04-20 Zhejiang University Novel daptomycin-producing streptomyces strain and use thereof

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