The long term goal of this project is to generate novel compounds for the treatment of fungal infections, particularly those in immuno- compromised patients. A library of analogs will be prepared based on the broad spectrum antifungal agents candicidin and FR-008. The library will constructed by manipulation of the gene cluster encoding the biosynthetic enzymes for FR-008. Selected genes encoding individual and groups of enzymatic activities from diverse polyketide synthase (PKS gene cluster scaffold. The resulting engineered PKS gene clusters will be expressed in a specially constructed streptomyces host/vector system. The analog library generated by this novel """"""""Combinatorial Biosynthesis"""""""" technology will provide an attractive alternative to the search for new antifungal natural products, and should prove extremely valuable as a source of drug leads. Phase I of this project will demonstrate the feasibility of building an analog library based on candicidin/R-008. The first three modules of the FR-008 PKS gene cluster and genes encoding starter unit synthesis and activation will be functionally expressed in the heterologous streptomyces host.
