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Streptomyces roseosporus and method for producing daptomycin by utilizing combined precursor

A technology of Streptomyces roseospora and daptomycin, which is applied in the field of biopharmaceuticals, can solve the problems of resource waste, high production cost, and increased foam, and achieve the effect of reducing resource waste, production cost, and extraction difficulty

Active Publication Date: 2012-11-28
鲁南新时代生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent U.S.Pat.No.4885243 discloses a method for producing daptomycin by fed-batch fermentation, which stimulates the side chain n-decanoyl of the synthetic daptomycin by adding n-decanoic acid, because n-decanoyl Acid is easy to solidify at the fermentation temperature. This method uses methyl oleate as a solvent to dissolve n-decanoic acid, but methyl oleate is hardly utilized by the production bacteria. This method causes serious waste of resources and significantly increases the difficulty and difficulty of downstream extraction. extraction cost
[0006] In the patent US.20100047873A1, Gianluca BETRETTI adopts the addition of n-decyl aldehyde instead of the addition of n-decanoic acid and methyl oleate composition as a precursor for fermentative production of daptomycin, but it is easy to cause fermentation when adding n-decyl aldehyde Foam increases during the process, resulting in low utilization efficiency of the fermenter
[0007] Fermentation methods are widely used in the production of daptomycin in China, but the yield of daptomycin is low, resulting in high production costs

Method used

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  • Streptomyces roseosporus and method for producing daptomycin by utilizing combined precursor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Streptomyces roseosporus. NTG1206 was used in a 50L fermenter to produce daptomycin by adding capric acid and methyl oleate.

[0034] 1 Preparation of liquid fermentation medium

[0035] Seed medium (g / L): dextrin 25, glucose 5, soybean meal 18, yeast powder 5, KCl0.2, FeSO 4 ·7H 2 O0.001, adjust the pH to 7.2 with 20% NaOH. Sterilize at 121°C for 30min.

[0036] Fermentation medium (g / L): dextrin 50, glucose 1.0, soybean meal powder 20, yeast powder 5.0, sugarcane molasses 7.0, Fe(NH 4 ) 2 (SO 4 ) 2 .6H 2 O0.8, KCl0.2, defoamer 0.5. Adjust the pH to 7.2 with 20% NaOH. Sterilize at 121°C for 30min.

[0037] 2 Fermentation process

[0038] (1) Streptomyces roseosporus. NTG1206 was inoculated on the slant medium, cultured aerobically at 30°C for 10 days, and the mature spores were prepared into glycerol tubes, which were stored at low temperature.

[0039] (2) Inoculate the bacterium solution preserved in step (1) into the seed medium of the shake flask, and sha...

Embodiment 2

[0045] Streptomyces roseosporus. NTG1206 was used in a 50L fermenter to produce daptomycin by adding decanal.

[0046] 1 Culture medium is the same as in Example 1.

[0047] 2 Fermentation process

[0048] In the fermentation process, a 50L fermentation tank has a liquid filling capacity of 30L, and all the other are the same as in Comparative Example 1.

[0049] After 30 hours of fermentation and cultivation, decanal was added at a rate of 0.15 g / L.h.

[0050] Daptomycin was detected by Shimadzu LC-20A liquid chromatograph, and appropriate amount of dextrin and yeast powder solution were added during the fermentation process. The titer of daptomycin was 1470 mg / L after 192 hours of fermentation, and the volume of the fermentation broth was 26 L.

[0051] The precursor was added for 48 hours, and the morphology of the bacteria was observed under a microscope, and no obvious vacuoles and hyphae were broken.

Embodiment 3

[0053] Streptomyces roseosporus. NTG1206 was used in a 50L fermenter to produce daptomycin by adding capric acid and decanal.

[0054] 1 Culture medium is the same as in Example 1.

[0055] 2 Fermentation process

[0056] (1) Streptomyces roseosporus. NTG1206 was inoculated on the slant medium, cultured aerobically at 30°C for 10 days, and the mature spores were prepared into glycerol tubes, which were stored at low temperature.

[0057] (2) Inoculate the bacterium solution preserved in step (1) into the seed medium of the shake flask, and shake and cultivate at 30°C and 230rpm for 30-48h.

[0058] (3) Inoculate the mature bacterial liquid from (2) into the fermentation medium (50L fermenter, liquid volume 35L) according to the inoculum volume of 1-5% of the medium volume of the fermenter. Fermentation conditions: 30°C, ventilation The volume is 1vvm, the stirring speed is 150rpm-350rpm, and the tank pressure is 0.05mpa. The pH was controlled at 6.5 with ammonia water.

[...

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Abstract

The invention discloses streptomyces and a method for producing daptomycin by utilizing the streptomyces. The strain is collected in China General Microbiological Culture Collection Center with the collection number of CGMCC No. 5956, the streptomyces CGMCC No. 5956 can be cultured under appropriate fermentation conditions, and a composition of decanoic acid and decyl aldehyde is added as a precursor for producing the daptomycin. By adopting the method for producing the daptomycin by utilizing the streptomyces, disclosed by the invention, a target product, namely the daptomycin has the advantages of high valence, high utilization rate of resources and low production cost, and is conductive to industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and in particular relates to Streptomyces roseosporus. and a method for producing daptomycin by using combined precursors. Background technique [0002] Daptomycin is a cyclic lipopeptide extracted from the fermentation broth of Streptomyces (S. reseosporus). It not only has a novel chemical structure, but also has a different mode of action from any approved antibiotic. : It can destroy the function of bacterial cell membrane in many ways, thus killing Gram-positive bacteria rapidly. In addition to acting on most clinically relevant Gram-positive bacteria, daptomycin is also potent in vitro against isolates that have been resistant to methicillin, vancomycin, and linezolid. active. The structure of daptomycin is shown below: [0003] [0004] U.S. Pat. No. 4,331,594 and U.S. Pat. No. 4,800,157 respectively first reported the method of producing daptomycin by submerged fermentation using S...

Claims

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Application Information

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IPC IPC(8): C12N1/20C12P21/02C12R1/465
Inventor 赵志全郭朝江夏燕王召娜
Owner 鲁南新时代生物技术有限公司
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