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-lactamase. The combination of clavulanic acid and amoxicillin has been used in human therapy extensively. The purpose of this study is to investigate the role of ammonium ion in the ferment culture, to explore the effect of precursors on the biosynthesis of clavulanic acid using S. clauvligerus in fed-batch fermentations and to seek out the optimal values of the parameters of the fermenter operation. A regularly intermittent feeding of ammonium ion improved the growth rate of S. clauvligerus but the biosynthesis of clavulanic acid was inhibited. The result of intermittent feeding of ornithine and glycerol in terms of maximum production of clavulanic acid was better than that of feeding of arginine and glycerol. The optimum operation condition of fermenter culture was 700 rpm of agitation rate and 2 l/min of aeration rate. In fermenter culture, the controlling glycerol concentration between 1~4 g/l and coupling with intermittent feeding of ornithine resulted in a maximum production of clauvlanic acid of 525 mg/l, which was 1.25 times that obtained in batch culture.