Suppression of <i>Staphylococcus aureus</i> virulence by a small-molecule compound.

Abstract

Emerging antibiotic resistance among bacterial pathogens has necessitated the development of alternative approaches to combat drug-resistance-associated infection. The abolition of <i>Staphylococcus aureus</i> virulence by targeting multiple-virulence gene products represents a promising strategy for exploration. A multiplex promoter reporter platform using <i>gfp</i>-<i>luxABCDE</i> dual-reporter plasmids with selected promoters from <i>S. aureus</i>-virulence-associated genes was used to identify compounds that modulate the expression of virulence factors. One small-molecule compound, M21, was identified from a chemical library to reverse virulent <i>S. aureus</i> into its nonvirulent state. M21 is a noncompetitive inhibitor of ClpP and alters α-toxin expression in a ClpP-dependent manner. A mouse model of infection indicated that M21 could attenuate <i>S. aureus</i> virulence. This nonantibiotic compound has been shown to suppress the expression of multiple unrelated virulence factors in <i>S. aureus</i>, suggesting that targeting a master regulator of virulence is an effective way to control virulence. Our results illustrate the power of chemical genetics in the modulation of virulence gene expression in pathogenic bacteria.