Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus.

Mike LA, Dutter BF, Stauff DL, Moore JL, Vitko NP, Aranmolate O, Kehl-Fie TE, Sullivan S, Reid PR, DuBois JL, Richardson AR, Caprioli RM, Sulikowski GA, Skaar EP
Proc Natl Acad Sci U S A. 2013 110 (20): 8206-11

PMID: 23630262 · PMCID: PMC3657828 · DOI:10.1073/pnas.1303674110

Staphylococcus aureus is a significant infectious threat to global public health. Acquisition or synthesis of heme is required for S. aureus to capture energy through respiration, but an excess of this critical cofactor is toxic to bacteria. S. aureus employs the heme sensor system (HssRS) to overcome heme toxicity; however, the mechanism of heme sensing is not defined. Here, we describe the identification of a small molecule activator of HssRS that induces endogenous heme biosynthesis by perturbing central metabolism. This molecule is toxic to fermenting S. aureus, including clinically relevant small colony variants. The utility of targeting fermenting bacteria is exemplified by the fact that this compound prevents the emergence of antibiotic resistance, enhances phagocyte killing, and reduces S. aureus pathogenesis. Not only is this small molecule a powerful tool for studying bacterial heme biosynthesis and central metabolism; it also establishes targeting of fermentation as a viable antibacterial strategy.

MeSH Terms (21)

Animals Anti-Bacterial Agents Bacterial Proteins Chromatography, High Pressure Liquid Combinatorial Chemistry Techniques Drug Design Fermentation Gene Expression Regulation, Bacterial Glycolysis Heme Heme Oxygenase (Decyclizing) Inhibitory Concentration 50 Leukocytes Mass Spectrometry Mice Microscopy, Electron, Scanning Naphthols Phagocytes Pyrazoles Staphylococcal Infections Staphylococcus aureus

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