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Fermentation process to produce clavulanic acid at a low concentration of free amino acids

A technology of free amino acid and clavulanic acid, applied in fermentation, organic chemistry, bacteria, etc., can solve the problem of protein inhomogeneity

Inactive Publication Date: 2001-08-15
DSM NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The obvious disadvantage is the heterogeneity of the protein, and generally the irreproducible quality associated with these complex nutrients

Method used

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  • Fermentation process to produce clavulanic acid at a low concentration of free amino acids
  • Fermentation process to produce clavulanic acid at a low concentration of free amino acids
  • Fermentation process to produce clavulanic acid at a low concentration of free amino acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Comparing batch fermentations of clavulanic acid using protein, protein hydrolyzate and protein extract

[0029] Streptomyces clavulus ATCC 27064 was modified for use in multiple rounds of classical mutagenesis (UV, nitrosoguanidine (NTG)) and selection for clavulanic acid production in shake flask cultures using the art-known imidazole method Production of clavulanic acid. The vegetative hyphae of this strain grown in tryptone soy broth medium (TSB-medium) at 28°C in a shaker incubator with a rotation speed of 280 rpm for 48 hours were stored frozen at -80°C .

[0030] Inoculate 1 ml of frozen mycelium into 100 ml of sterilized (30 min, 121°C) 1 H 2 O, 15-30 g / l bacto tryptone, 15-30 g / l bacto peptone, 1-10 g / l bacto soy peptone, 1-5 g / l potassium dihydrogen phosphate and 0.2 g / l synthetic antifoam in the pre-medium.

[0031] After 72 hours of incubation at 27°C to 28°C, 2.5% of this preculture was transferred to sterile production medium containing 2.5 g of all co...

Embodiment 2

[0035] Clavulanic acid fermentation in low-level free glutamate medium Batch fermentation of clavulanic acid

[0036] Streptomyces clavulus ATCC 27064 was pre-cultivated for 26 hours at a temperature of 28°C in a shaker incubator at 220 rpm, the initial pH was 6.8, and the culture medium contained 5 to 30 g / L glycerol, 5 to 30 g / L soy peptone, 2 to 6 g / L sodium chloride, and 0.5 to 3 g / L calcium carbonate.

[0037] Inoculate the preculture at 10% volume into 1 L containing 10-30 g / L glycerol, 0.5 to 3 g / L KH 2 PO 4 , 1 to 3 g / L (NH 4 ) 2 SO 4 , 15-25 g / l monosodium glutamate, 0.05 to 0.2 g / l FeSO 4 .7H 2 O, 0.1 to 1 g / L MgSO 4 .7H 2 O, 10-20 g / L 2-(N-morpholino)propanesulfonic acid (MOPS), 0.2-1 g / L basildon antifoam agent, and appropriate trace element solutions in a chemically defined medium. The pH was adjusted to 6.8 with 4N NaOH. The secondary preculture was grown for 20 hours at a temperature of 28° C. in a shaker incubator at 220 rpm, with an initial...

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Abstract

An improved method for the production of secondary metabolites by the fermentation of a Streptomyces strain has been disclosed. If the concentration of free amino acids is kept low, a surprisingly high yield is obtained.

Description

field of invention [0001] The present invention relates to the field of fermentative production of secondary metabolites by strains of the genus Streptomyces on a suitable medium containing carbon and nitrogen sources. Background of the invention [0002] Fermentation by microorganisms of the genus Streptomyces produces a large number of diverse secondary metabolites such as β-lactams, polyketides and macrolides such as clavulanic acid, pimaricin and erythromycin. Clavulic acid is an important β-lactamase inhibitor produced by various microbial strains belonging to the genus Streptomyces, such as S. clavuligerus ATCC 27064, S. jumonjinensis (UK patent 1563103), Guilin Streptomyces (S. katsurahamanus) IFO13716 FERM 3944 (Japanese Patent No. 83009679B) and Streptomyces strain P6621 FERM2804 (Japanese Patent Application No. 55162993A). [0003] Clavulanic acid has been produced in large quantities, and the production conditions are being continuously op...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/43C07D503/00C12N1/20C12P17/18
CPCC12P17/188
Inventor W·T·A·M·德拉阿特P·克拉本
Owner DSM NV