Accelerating the Discovery of Antibacterial Compounds to Validate Drug Targets and Probe Cell Physiology of S. Aureus

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a Gram-positive pathogen identified by its resistance to beta-lactam antibiotics. In an era where drug-resistant infections are becoming harder and harder to treat, new antibiotics and strategies are needed to combat them. High-throughput screening is one common approach to discover new potential leads for drug development. However, identifying biologically active compounds that inhibit a pathway of interest is difficult and hit prioritization can be challenging. Using pathway-directed whole-cell screening, we rapidly identified biologically active small molecules of two virulence pathways in S. aureus: the wall teichoic acid (WTA) and D-alanylation (Dlt) pathways. In this thesis, we discuss: 1) the discovery of a new WTA inhibitor, targocil-II, that showed efficacy in a mouse infection model; 2) a method to rapidly identify inhibitors of nonessential pathways that led to the successful identification of a new inhibitor of the Dlt pathway called DBI-1; and 3) the use of DBI-1 and other Dlt pathway inhibitors as probe compounds to investigate cellular pathways in S. aureus. Using these inhibitors, we discovered interesting biology regarding the functions of LtaS, the S. aureus lipoteichoic acid synthase. These inhibitors are candidates for combination therapies with existing antibiotics to treat MRSA and are useful tools for probing S. aureus physiology.