Improved Production of Clavulanic Acid by Genetic Engineering of Streptomyces Clavuligerus
Clavulanic acid is a potent beta-lactamase inhibitor used to combat resistance to penicillin and cephalosporin antibiotics. There is a demand for high-yielding fermentation strains for industrial production of this valuable product. This invention describes genetic engineering of the glycolytic pathway in Streptomyces clavuligerus to partially block the flux of D-glyceraldehyde-3-phosphate (G3P) into the Krebs cycle. G3P is one of two primary metabolic precursors of clavulanic acid biosynthesis, and this diversion of carbon flux more than doubles production of this valuable natural product in the wild-type strain. This is the first reported application of genetic engineering to channel precursor flux to improve clavulanic acid production. Description (Set) Proposed Use (Set) Bacterial resistance only gets worse and the role of compounds like clavulanic acid for the treatment of resistance to beta-lactam antibiotics continues to grow. Clavulanic acid is more expensive than the penicillin it is combined with, so anything to drive down the cost of fermentation is extremely valuable. Moreover, commercial strains of Streptomyces clavuligerus are generated by traditional mutagenesis and selection - years of work. This invention describes a rational genetic engineering approach, which is distinguished from biosynthetic gene dosage experiments that are well-described in streptomyces, whereby the fundamental precursor carbon flux of the producing organism is been altered to improve clavulanic acid production.
Townsend, Craig A.
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