Project 1: Structure, function, and inhibition of SEDS-family peptidoglycan polymerases

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PROJECT SUMMARY Project 1: Structure, function, and inhibition of SEDS-family peptidoglycan polymerases The peptidoglycan cell wall is essential for viability and growth in nearly all bacteria, and drugs that interfere with cell wall assembly are among the most effective antibiotics. Building a peptidoglycan cell wall requires glycan strand elongation catalyzed by glycosyltransferase enzymes and peptide crosslinking catalyzed by penicillin- binding proteins (PBPs). In Project 1, we will investigate a newly discovered family of integral membrane peptidoglycan glycosyltransferase enzymes called shape, elongation, division and sporulation (“SEDS”) proteins. Proteins in the SEDS family are found in all bacteria with a peptidoglycan cell wall and they are essential for growth, making them ideal antibiotic targets. In this project, we will investigate SEDS protein function using a combination of structural biology and chemical biology approaches. Specifically, we will investigate 1) how SEDS proteins are allosterically activated by PBPs and catalyze peptidoglycan synthesis, 2) how a prototypical SEDS protein functions in the context of a large multi-protein cell elongation machine called the Rod complex, and 3) how SEDS proteins are organized and regulated in the divisome cell division machinery. Collectively, this project will lead to the development of a detailed mechanistic understanding of SEDS protein function as well as the discovery of new chemical inhibitors of this important protein class.