The soil microorganism Streptomyces makes over half of the antibiotics that are obtained from all microorganisms. The study of how antibiotics are made is a basic prerequisite for developing new antibiotics and new methods of producing antibiotics, as well as for understanding basic ecological processes in the soil microbiota. Nonactin is an antibiotic that is active against Gram positive bacteria, mycobacteria, and fungi and also blocks one of the major processes by which cancer cells are resistant to anti-cancer drugs. The microorganism Streptomyces griseus makes nonactin in fermentative culture although the exact details of this process are not presently understood. Current evidence suggests that nonactin is assembled by a number of proteins which work together as a large protein complex known as a polyketide synthase. The structure of nonactin is quite unusual in that it is made up of two forms of a precursor that are mirror images of each other. It is also not known how the organism achieves the synthesis of both mirror images of this precursor. The objectives of the research are to gain an understanding of how nonactin is made by a polyketide synthase and to determine how the formation of two mirror-image compounds is achieved and controlled. The project will use a multidisciplinary approach to study the polyketide synthase genes from Streptomyces griseus as well as the basic chemistry of the natural synthesis pathway. The research will determine which genes in the organism control the synthesis of each of the mirror image precursors and the exact manner in which these precursors are formed from simple organic acids. The basic information gained in the study of this unusual system will add to the body of existing knowledge of natural product synthesis. The long term goal of the research is to understand the natural synthesis pathways in sufficient detail that an organism can be rationally altered to produce any designed, target antibiotic by a fermentation process from cheap starting materials in an environmentally friendly manner.
