Mechanistic Studies and In Vivo Efficacy of an Oxadiazole-Containing Antibiotic

Methicillin-resistant Staphylococcus aureus (MRSA) infections are still difficult to treat, despite the availability of many FDA-approved antibiotics. Thus, new compound scaffolds are still needed to treat MRSA. The oxadiazole-containing compound, HSGN-94, has been shown to reduce lipoteichoic acid (LTA) in S. aureus, but the mechanism that accounts for LTA biosynthesis inhibition remains uncharacterized. Herein, we report the elucidation of the mechanism by which HSGN-94 inhibits LTA biosynthesis via utilization of global proteomics, activity-based protein profiling, and lipid analysis via multiple reaction monitoring (MRM). Our data suggest that HSGN-94 inhibits LTA biosynthesis via direct binding to PgcA and downregulation of PgsA. We further show that HSGN-94 reduces the MRSA load in skin infection (mouse) and decreases pro-inflammatory cytokines in MRSA-infected wounds. Collectively, HSGN-94 merits further consideration as a potential drug for staphylococcal infections.