Dual Inhibitor of Staphylococcus aureus Virulence and Biofilm Attenuates Expression of Major Toxins and Adhesins

Staphylococcus
aureus is a major
bacterial pathogen that invades and damages host tissue by the expression
of devastating toxins. We here performed a phenotypic screen of 35
molecules that were structurally inspired by previous hydroxyamide-based S. aureus virulence inhibitors compiled from commercial
sources or designed and synthesized de novo. One of the most potent
compounds, AV73, not only reduced hemolytic alpha-hemolysin
production in S. aureus but also impeded
in vitro biofilm formation. The effect of AV73 on bacterial
proteomes and extracellular protein levels was analyzed by quantitative
proteomics and revealed a significant down-regulation of major virulence
and biofilm promoting proteins. To elucidate the mode of action of AV73, target identification was performed using affinity-based
protein profiling (AfBPP), where among others YidC was identified
as a target.