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

• Type of Material: Article
• Authors: Barbara Hofbauer, Technische Universität München; Jan Vomacka, Technische Universität München; Matthias Stahl, Technische Universität München; Vadim S. Korotkov, Technische Universität München; Megan C. Jennings, Temple University; William M. Wuest, Emory University; Stephan A. Sieber, Technische Universität München
• Language: English
• Date: 2018-03-01
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Chemical Society
• Final Published Version (URL): https://doi.org/10.1021/acs.biochem.7b01271
• Title of Journal or Parent Work: Biochemistry
• Volume: 57
• Issue: 11
• Start Page: 1814
• End Page: 1820
• Grant/Funding Agency: German Academic Scholarship Foundation; Center for Integrated Protein Science Munich; National Institutes of Health; National Science Foundation; Federal Ministry of Education, Research, Germany
• Grant/Funding Information: The work was funded by the Center for Integrated Protein Science Munich (CIPSM) and by the Federal Ministry of Education, Research, Germany, FKZ: 031A131, National Science Foundation (CHE1755698), and the National Institutes of Health (DE025837, GM119426). M.S. was supported by the German Academic Scholarship Foundation. M.C.J. acknowledges a National Science Foundation predoc-toral grant (DGE-1144462).
• Keywords: bacterial pathogen; toxins; Adhesins; Staphylococcus aureus
• Subject - Topics: Chemical biology; Microbiology; Proteomics

Abstract

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.