title: Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus.
abstract: 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.
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Laura A
authors: LA
authors: Mike
authors: Brendan F
authors: BF
authors: Dutter
authors: Devin L
authors: DL
authors: Stauff
authors: Jessica L
authors: JL
authors: Moore
authors: Nicholas P
authors: NP
authors: Vitko
authors: Olusegun
authors: O
authors: Aranmolate
authors: Thomas E
authors: TE
authors: Kehl-Fie
authors: Sarah
authors: S
authors: Sullivan
authors: Paul R
authors: PR
authors: Reid
authors: Jennifer L
authors: JL
authors: DuBois
authors: Anthony R
authors: AR
authors: Richardson
authors: Richard M
authors: RM
authors: Caprioli
authors: Gary A
authors: GA
authors: Sulikowski
authors: Eric P
authors: EP
authors: Skaar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D005285:Fermentation; D015964:Gene Expression Regulation, Bacterial; D006019:Glycolysis; D006418:Heme / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007962:Leukocytes / Q000166:cytology; D013058:Mass Spectrometry; D051379:Mice; D008855:Microscopy, Electron, Scanning; D009284:Naphthols / Q000494:pharmacology*; D010586:Phagocytes / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009284:Naphthols; D011720:Pyrazoles; C582431:VU0038882; D006418:Heme; D006419:Heme Oxygenase (Decyclizing)
keywords: glycolysis; heme oxygenase; high-throughput screen (HTS); two-component system (TCS)
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