A Small Molecule Dual Inhibitor of agr Quorum Sensing and ATP Synthase Blocks Acute and Chronic Virulence Phenotypes in Staphylococcus aureus
Troy D. Vulpis, Jordan T. York, A.P. Clay, Thomas J. Polaske, Samuel W. Markovich, Kijeong Lee, Douglas H. Chang, Sean P. Palecek, David M. Lynn, John-Demian Sauer, Lloyd M. Smith, Helen E. BlackwellAbstract
The accessory gene regulator (agr) quorum-sensing system in Staphylococcus aureus plays a prominent role in acute infections caused by this common pathogen. 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 agr 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 agr or ATP synthase alone, suggesting that dual inhibition may have an additive effect on ablating intracellular survival. This work demonstrates the utility of a single chemical modulator to attenuate S. aureus pathogenesis via two nonessential pathways and suggests a pathway toward nonbactericidal virulence control.