A Small Molecule Dual Inhibitor of agr Quorum Sensing and ATP Synthase Blocks Acute and Chronic Virulence Phenotypes in Staphylococcus aureus

In contrast, ATP synthase affects the ability of S. aureus to establish chronic infections and persist as small colony variants. In this study, we report that a synthetic small molecule, CP-20, is capable of dually inhibiting <i>agr</i> and ATP synthase.

We demonstrate CP-20’s ability to counteract key virulence phenotypes associated with both pathways, including hemolysis, biofilm formation, and antibiotic resistance. We also show that CP-20 facilitates more efficient clearance of S. aureus by murine macrophages than genetic inactivation of either <i>agr</i> or ATP synthase alone, suggesting that dual inhibition may have an additive effect on ablating intracellular survival.