Abstract
Clavulanic acid is one of the fermentation products through secondary metabolism by Streptomyces clavuligerus. It is also a specific and irreversible inhibitor of a wide range of bacterial β-lactamases. Clavulanic acid has been used in human therapy for several years in combination with amoxicillin. The purpose of this study is to investigate the effects of different precursors and soy meal extract on the biosynthesis of clavulanic acid using S. clavuligerus in batch and fed-batch fermentations. A regularly intermittent feeding strategy was employed to obtain the maximum productivity of clavulanic acid when different feed medium was used to improve the production. The medium containing soy meal extract with the TKN concentration of 0.59 g/L was optimum. Intermittently feeding the medium containing glycerol to the shake flask cultures resulted in the maximum production of clavulanic acid being 2.3-fold higher than that with no additional feeding. Intermittent feeding simultaneously with glycerol and ornithine (or arginine) resulted in the maximum production of clavulanic acid being 2.7-fold (or 2.8-fold) higher than that with no feeding. The fed batch result indicates that glycerol is an important precursor of the β-lactam moiety(C-5,C-6, and C-7), whereas ornithine (or arginine) is an important precursor of C5-moiety. Both glycerol and ornithine (or arginine) exert a stimulation of the biosynthesis of clavulanic acid, and they are efficiently incorporated into clavulanic acid.