Georgia Institute of Technology

Nature has provided us with an arsenal of agents that have proven clinically useful in the treatment of many human diseases, and this is particularly apparent for infectious diseases and cancer. Resistance to current anticancer and antimicrobial chemotherapies will always necessitate the discovery and development of additional therapeutic compounds, both by screening of natural products and by synthetic design. Biosynthetic engineering is a promising tool that could be coupled with these proven techniques to generate novel bioactive metabolites. Dr. Kelly's group examines natural products biosynthesis and its applications from chemical and microbiological perspectives.

A number of naturally occurring antibiotics are biosynthesized by one of two classes of large, multimodular, often multi-enzyme complexes: either nonribosomal peptide synthetases (NRPSs) or polyketide synthases (PKSs). For every extender unit incorporated into the final product, there is a corresponding module in the PKS or NRPS. The modules are further subdivided into discrete catalytic and structural domains that each catalyze a single chemical step required to incorporate a monomeric unit into the polyketide or nonribosomal peptide. Following generation of a core skeleton, additional enzymatic transformations may be required for the bioactivity of the final metabolite. The modular NRPS and PKS systems are extremely attractive targets for biochemical and genetic manipulation to generate novel bioactive metabolites, and a body of work has emerged supporting the feasibility of this application. Before full exploitation of these approaches can be realized, a thorough understanding of the enzymes of interest and factors contributing to catalysis is paramount.

Dr. Kelly's group is interested in the biosynthesis of polyketide and nonribosomal peptide antibiotics in addition to the biosynthesis of post-translationally modified peptide antibiotics. We aim to understand the assembly of central scaffolds that appear in families of metabolites that vary in their biological activity according to unique peripheral modifications. This requires a detailed understanding of the enzymes responsible for construction of these molecules, including their catalytic mechanism and substrate specificity. Strategies and techniques from organic chemistry, biochemistry, molecular biology, and microbiology will be infused together to accomplish this task. Ultimately, we will apply the information gleaned from these studies to direct the biosynthesis of designer metabolites possessing antimicrobial or anticancer activities.