A Small Molecule Inhibitor of the Staphylococcus aureus agr Quorum Sensing System with Low-Nanomolar Potency

Abstract

The accessory gene regulator (agr) quorum sensing system regulates virulence in certain common Gram-positive bacteria, including Staphylococcus aureus. Small molecules that block agr have been reported, but most have modest potencies and warrant further mechanistic characterization. Herein, we report a structure–function study on CP-20, a compound recently shown to inhibit agr in S. aureus by targeting the histidine kinase AgrC. We designed a robust new synthetic route to the CP-20 scaffold, generated a collection of CP-20 analogues, and evaluated their activities in cell-based agr reporter and phenotypic assays. These investigations led to the discovery of a compound, CP-20t, which inhibits agr in S. aureus with low-nanomolar potency and acts on AgrC. CP-20t represents, to our knowledge, the most potent small molecule inhibitor of agr known—bridging the almost 1000-fold potency gap between peptide- and small molecule-based inhibitors—and is a powerful tool to study quorum sensing in S. aureus.