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

Laura A. Mike, Brendan F. Dutter, Devin L. Stauff, Jessica L. Moore, Nicholas P. Vitko, Olusegun Aranmolate, Thomas E. Kehl-Fie, Sarah Sullivan, Paul R. Reid, Jennifer L. DuBois, Anthony R. Richardson, Richard M. Caprioli, Gary A. Sulikowski, Eric P. Skaar

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)8206-8211
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number20
DOIs
StatePublished - May 14 2013
Externally publishedYes

Keywords

  • Glycolysis
  • Heme oxygenase
  • High-throughput screen (HTS)
  • Two-component system (TCS)

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus'. Together they form a unique fingerprint.

Cite this