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 C3 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 C5 precursor. Fluxes through reactions leading to biosynthesis of precursors of the C3 moiety of the clavulanic acid molecule, correlated with flux to clavulanic acid when the dilution rate was varied.