Heterocycles in natural products: Enzymes, pathways, and chemistry

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Molecules isolated from living organisms are some of the most chemically complex and medicinally relevant compounds ever isolated. These natural product molecules play critical roles as antibiotics and other drugs. My research group is interested in understanding how nature constructs natural products, and our long-term goal is to harness this knowledge to develop new molecules and to understand how novel enzymes function. In this program, we will use indolmycin, a unique antibiotic, with translational potential as an agent against methicillin-resistant Staphylococcus aureus (MRSA), as a starting point to elucidate fundamental bioorganic chemistry. Previous work in my group identified the indolmycin gene cluster and the roles of several unique enzymes in building this unique structure. These prior results set the stage to elucidate new enzyme mechanisms and investigate related systems identified from genomic mining. Furthermore, we are now positioned to develop new molecules by combining techniques from organic chemistry, enzymology, and genetic engineering. In this program, we will pursue three related objectives: first, we will use X-ray crystallography to solve the structures of indolmycin biosynthetic enzymes. Several of the indolmycin enzymes catalyze reactions that are unprecedented, and we want to understand how they work. By generating molecular “blueprints” for these enzymes, we will understand the architecture of these proteins and set the stage for engineering them to do new reactions. Second, we will elucidate three new pathways related to indolmycin. Using bioinformatics tools, we have discovered three gene clusters that have genes related to the indolmycin genes. Our goals are to understand the enzymes encoded by these new gene clusters and to elucidate the products of these new pathways. Third, we will generate a library of indolmycin derivatives by combining techniques from chemistry and biology. This work will harness and engineer the indolmycin gene cluster to make molecules that we can test for their antibiotic activity. Overall, our work will provide fundamental insights into enzymology, biosynthesis, and bioorganic chemistry and provide sustainable access to library of new indolmycin-like molecules to enable downstream translational efforts to develop new antibiotics.