Characterization of natural product inhibitors of quorum sensing reveals competitive inhibition of <i>Pseudomonas aeruginosa</i> RhlR by <i>ortho</i> -vanillin

Abstract

Quorum sensing (QS) regulates many aspects of bacterial pathogenesis and has attracted much interest as a target for anti-virulence therapies over the past 30 years, for example, antagonists of the LasR and RhlR QS receptors in <i>Pseudomonas aeruginosa</i>. Potent and selective QS inhibitors remain relatively scarce. However, natural products have provided a bounty of chemical scaffolds with anti-QS activities, but their molecular mechanisms are poorly characterized. The current study serves to fill this void by examining the activity of an important and wide-spread class of natural product QS modulators, benzaldehydes, and related derivatives, in LasR and RhlR. We demonstrate that <i>ortho</i>-vanillin can act as a competitive inhibitor of RhlR, a receptor that has emerged and may supplant LasR in certain settings as a target for <i>P. aeruginosa</i> QS control. The results and insights provided herein will advance the design of chemical tools to study QS with improved activities and selectivities.