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.
Hofbauer, B., Vomacka, J., Stahl, M., Korotkov, V.S., Jennings, M., Wuest, W., Sieber, S.A., "A dual inhibitor of Staphylococcus aureus virulence and biofilm attenuates expression of major toxins and adhesins", Biochemistry 2018, 57, 1814–1820.
Copyright 2018 American Chemical Society. Reprinted with permission.