Enhancement of nystatin production by redirecting precursor fluxes after disruption of the tetramycin gene from Streptomyces ahygroscopicus

Complete and independent tetramycin and nystatin gene clusters containing varying lengths of type I polyketide synthase (PKS) genes were isolated from Streptomyces ahygroscopicus, a producer of tetramycin (a tetraene) in large amounts and nystatin A1 (a heptaene) in small amounts. Tetramycin was similar to pimaricin, and nystatin A1 was similar to amphotericin. All these polyene macrolide antibiotics possessed the same macrolactone ring biosynthesized from coenzyme A precursors by PKSs but had different number of atoms in the macrolactone ring and side groups. Because tetramycin and nystatin shared limited coenzyme A precursors in the same producer organism, blocking the consumption of precursors in tetramycin pathway may increase the coenzyme A pool. Thus, we genetically manipulated the tetramycin PKS to enhance nystatin production. The type I PKS ttmS1 gene mutant abolished production of tetramycin and had a beneficial effect on the production of nystatin A1. For the mutant, the yield of nystatin A1 was increased by 10-fold compared to that of the wild-type. Thus, deletion of the tetramycin pathway redirected precursor metabolic fluxes and provided an easy genetic approach to manipulate organisms and to increase production levels of a precise target.