Biosynthesis of the polyene antifungal antibiotic nystatin in Streptomycesnoursei ATCC 11455: analysis of the gene cluster and deduction of the biosynthetic pathway

Background: The polyene macrolide antibiotic nystatin produced by Streptomy ces noursei ATCC 11455 is an important antifungal agent. The nystatin molec ule contains a polyketide moiety represented by a 38-membered macrolactone ring to which the deoxysugar mycosamine is attached. Molecular cloning and characterization of the genes governing the nystatin biosynthesis is of con siderable interest because this information can be used for the generation of new antifungal antibiotics. Results: A DNA region of 1 23,580 base pairs from the S. noursei ATCC 11 45 5 genome was isolated, sequenced and shown by gene disruption to be involve d in nystatin biosynthesis. Analysis of the DNA sequence resulted in identi fication of six genes encoding a modular polyketide synthase (PKS), genes f or thioesterase, deoxysugar biosynthesis, modification, transport and regul atory proteins. One of the PKS-encoding genes, nysC, was found to encode th e largest (11,096 amino acids long) modular PKS described to date. Analysis of the deduced gene products allowed us to propose a model for the nystati n biosynthetic pathway in S. noursei. Conclusions: A complete set of genes responsible for the biosynthesis of th e antifungal polyene antibiotic nystatin in S. noursei ATCC 11455 has been cloned and analyzed. This represents the first example of the complete DNA sequence analysis of a polyene antibiotic biosynthetic gene cluster. Manipu lation of the genes identified within the cluster may potentially lead to t he generation of novel polyketides and yield improvements in the production strains.