Manipulation of the physiology of clavulanic acid biosynthesis with the aid of metabolic flux analysis

Feeding a chemostat culture of Streptomyces clavuligerus with a combination of amino acids, formulated with the aid of metabolic flux analysis (MFA), resulted in an 18-fold increase in antibiotic (clavulanic acid) yield compared to the non-fed control. MFA of cultures fed with single amino acids was consistent with availability of the C-3 precursor of clavulanic acid limiting antibiotic yield in phosphate-limited cultures, suggesting that the urea cycle, present in this species, was capable of providing excess C-5 precursor. Fluxes through reactions leading to biosynthesis of precursors of the C-3 moiety of the clavulanic acid molecule, correlated with flux to clavulanic acid when the dilution rate was varied. (c) 2006 Published by Elsevier Inc.