Discovery of Bioactive Inhibitors of Two Distinct Cell Envelope Biosynthesis Pathways in Staphylococcus Aureus

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of antibiotic-resistant community- and hospital-acquired infections, and options for treating these infections are becoming increasingly limited. In order to address this imminent public health threat, we must develop efficient strategies to identify new antibiotics that inhibit novel targets or to discover compounds that can re-sensitize MRSA to beta-lactams. In this thesis I describe a pathway-directed high-throughput screen to identify compounds that inhibit cell envelope biosynthetic pathways that play fundamental roles in S. aureus physiology. This screen identified a late-stage inhibitor of the wall teichoic acid biosynthesis pathway that is lethal to both MSSA and MRSA strains. It also identified an inhibitor of an early step in the lipoteichoic acid biosynthesis pathway. This inhibitor prevents the formation of diglucosyl-diacylglycerol, causing structural changes in lipoteichoic acids that result in cell division defects and impaired pathogenesis. I show that this compound strongly re-sensitizes MRSA to beta-lactams, suggesting that inhibitors of this pathway may be useful in combination with beta-lactams to treat MRSA infections. This work provides a roadmap for the discovery and characterization of compounds active against S. aureus that target proteins in a desired area of biological space.