Process for the production of clavulanic acid and/or salts there

Details Process for the production of clavulanic acid and/or salts there Process for the production of clavulanic acid and/or salts there

1997-09-15

2000-08-08

Marx, Irene

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing compound having a 1-thia-4-aza-bicyclo

435118, 435119, 435120, 435886, C12P 3700

Patent

active

061000523

DESCRIPTION:

BRIEF SUMMARY
A process is described for the production of clavulanic acid and/or its salts by means of a fermentation with selected strains of Streptomyces clavuligerus with a strict control of the concentration of soluble phosphate present during the fermentation and with the optional use of carbon sources such as lipids, preferably triglycerides.


PRIOR ART

Clavulanic acid is a molecule of formula ##STR1## whose usefulness is based on its capacity to inhibit the enzymes called beta-lactamases, which are possessed by some Gram-positive and Gram-negative pathogenic microbes such as Escherichia coli, Klebsiella aerogenes, and the like, and which, due to their action, endows them with resistance to some beta-lactam antibiotics. As a result, clavulanic acid mixed with the said antibiotics increases their antibacterial spectrum.
It is known that the production of clavulanic acid is performed by several strains belonging to the genus Streptomyces, such as, for example, Streptomyces clavuligerus ATCC 27064, Streptomyces jumonjinensis NRRL 5741, and the like.
As has already been disclosed in earlier patents (European Patent 0,182,522 B1), the production of clavulanic acid may be increased in batch fermentation when an assimilable carbon source such as, for example, glycerol or maltose is added during the fermentation also instead of only being added initially. However, this increase in production obtained in this way is fairly low. Accordingly, an objective of the present invention is to procure a process for obtaining clavulanic acid and/or its salts with a production which is plainly greater than that obtained by the processes known in the prior art.
Many authors have demonstrated the inhibitory effect of phosphate on the production of antibiotics (Martin, J. F., 1977, Adv. Biochem. Eng. 6:105-127). Specifically, an inhibition of phosphate on the synthesis of cephalosporins by Streptomyces clavuligerus has been found (Lubbe, C. et al. 1985, Arch. Microbiol. 140:317-320 and Lubbe, C. et al. 1984, FEMS Microbiol. Lett. 25:75-79; Aharonowithz, Y. et al. 1977, Arch. Microbiol. 115:169-173; Jhang, J. et al. 1989, FEMS, 57:145-150), and also an inhibitory effect of phosphate on the synthesis of clavulanic acid by the said microorganism (Lebrihi, A. et al. 1987, Appl. Microbiol. Biotechnol. 26:130-135; Romero, J. et al. 1984, Appl. Microbiol. Biotechnol. 20:318-325). However, contrary to the findings reported in the above papers, we have found, surprisingly, instead of a negative effect of phosphate on the production of clavulanic acid, a substantial increase in the production of clavulanic acid and/or its salts when the soluble phosphate level in the culture medium reaches an optimal range and is maintained in the said range. What is more, we have found that a strict control of the concentration of soluble phosphate in the culture medium has a greater influence on the increase in production of the system than the actual addition of nutrients. A batch or semi-continuous (fed-batch) culture of Streptomyces clavuligerus was used for the production of clavulanic acid, as well as other antibiotics or molecules typical of secondary metabolism. For the purposes of this specification, the term batch culture indicates a fermentation in which the nutrients are introduced into the culture medium only initially and the broth is extracted from the fermentation tank only at the end of the process. The term semi-continuous (fed-batch) culture implies a fermentation in which the nutrients are introduced into the culture medium not only initially, but also throughout the fermentation, and the broth is extracted from the fermentation tank only at the end of the process. The process of batch or fed-batch production of clavulanic acid displays some special features of fermentation, so that a significant increase in viscosity is initially produced, with the resulting difficulty of maintaining an acceptable level of dissolved oxygen for prolonging the production phase for longer periods of time. Consequently, a fragmentation of the mycelium, a decre

REFERENCES:
patent: 4110165 (1978-08-01), Cole
Fang et al., J. Ind. Microbiol., vo. 15 (5), p. 407-410, 1995.
Romero, J. Et al. "Dissociation of cephamycin and clavulanic acid biosynthesis in Streptomyces Clavuligerus." Applied Microbiology and Biotechnology, vol. 20 (1984), pp. 318-325.
Lebrihi, A. Et al. "Phosphate repression of cephamycin and clavulanic acid production by Streptomyces clavuligerus." Applied Microbiology and Biotechnology, vol. 26, (1987), pp. 130-135. AT 400846 B (Fermic S.A.) Feb. 15, 1996.

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