Biology

Swapnil V. Ghodge , PhD
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill

New antibiotics are urgently needed to tackle the rising menace of drug-resistant pathogens. At present, the most extensive and convenient resource available is the sequenced genomes of microorganisms. We aim to uncover novel natural products from microbial genomes by using a systematic strategy based on biochemical characterization of enzymes involved in antibiotic biosynthesis, and protein sequence homology to guide the selection of candidate enzymes from previously uncharacterized biosynthetic pathways. In addition to uncovering natural secondary metabolites, we intend to develop libraries of analogs of known antibiotics to facilitate facile activity screening. We are developing new building blocks for rapid diversification of structures, and engineering enzymes for late stage non-natural modifications. The stated research goals are being pursued within the domain of ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotics.

I will discuss the reconstitution and characterization of PaaA, an enzyme which catalyzes an unprecedented reaction en route to the biosynthesis of Pantocin A. Enzymes homologous to PaaA were found to be encoded in diverse operons, which may be leads to discovering new secondary metabolites. I will also present our ongoing efforts toward generating libraries of thiopeptide antibiotics, and carrying out non-natural enzymatic modifications like cyclopropanation on complex scaffolds using enzyme catalysis.