(Principal Investigator's): Natural products, small molecules that do not appear to play a role in an organism's internal economy, are a key link between chemistry and biology. Chemical biology, a field that uses chemical tools to probe biological functions, makes extensive use of natural products. Natural products have provided both the reagents that helped define cellular processes and the pharmaceutical agents that treat human diseases. One recent analysis found that half of the drugs currently used in cancer chemotherapy are natural products or their derivatives. Other analyses have highlighted the therapeutic potential of naturally occurring antibiotics to combat infectious diseases. A comprehensive natural products program needs interesting source organisms, relevant screens to find the most important compounds from those organisms, and a way of understanding how the natural products work. In addition to approaches that have been successfully used in the past, the proposed work encompasses new approaches to all three aspects of natural products. Novel source organisms: Fewer than 1 percent of soil microbes, the traditional source of pharmaceutical agents, can be grown with current methods. Bacterial artificial chromosome (BAC) libraries prepared from microbial DNA extracted from soil samples will be used to examine the natural products of these completely unexplored organisms. Novel screens: A series of yeast (Saccharomyces cerevisiae) deletion mutants, yeast in which a gene has been knocked out, will be used to screen for highly specific and cell permeable agents. Structural studies of natural products complexed with their macromolecular targets: An atomic resolution X-ray crystallographic analysis of a natural product-protein complex elucidates the three-dimensional structure of the natural product, clarifies the mechanism by which it acts, and suggests ways to improve its specificity and/or potency.
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