Sulfide homeostasis and nitroxyl intersect via formation of reactive sulfur species in Staphylococcus aureus

Hui Peng, Jiangchuan Shen, Katherine A. Edmonds, Justin L. Luebke, Anne K. Hickey, Lauren D. Palmer, Feng Ming James Chang, Kevin A. Bruce, Thomas E. Kehl-Fie, Eric P. Skaar, David P. Giedroc

Research output: Contribution to journalArticlepeer-review

Abstract

Staphylococcus aureus is a commensal human pathogen and a major cause of nosocomial infections. As gaseous signaling molecules, endogenous hydrogen sulfide (H2S) and nitric oxide (NO·) protect S. aureus from antibiotic stress synergistically, which we propose involves the intermediacy of nitroxyl (HNO). Here, we examine the effect of exogenous sulfide and HNO on the transcriptome and the formation of low-molecular-weight (LMW) thiol persulfides of bacillithiol, cysteine, and coenzyme A as representative of reactive sulfur species (RSS) in wild-type and ΔcstR strains of S. aureus. CstR is a per- and polysulfide sensor that controls the expression of a sulfide oxidation and detoxification system. As anticipated, exogenous sulfide induces the cst operon but also indirectly represses much of the CymR regulon which controls cysteine metabolism. A zinc limitation response is also observed, linking sulfide homeostasis to zinc bioavailability. Cellular RSS levels impact the expression of a number of virulence factors, including the exotoxins, particularly apparent in the ΔcstR strain. HNO, like sulfide, induces the cst operon as well as other genes regulated by exogenous sulfide, a finding that is traced to a direct reaction of CstR with HNO and to an endogenous perturbation in cellular RSS, possibly originating from disassembly of Fe-S clusters. More broadly, HNO induces a transcriptomic response to Fe overload, Cu toxicity, and reactive oxygen species and reactive nitrogen species and shares similarity with the sigB regulon. This work reveals an H2S/NO· interplay in S. aureus that impacts transition metal homeostasis and virulence gene expression.

Original languageEnglish (US)
Article numbere00082-17
JournalmSphere
Volume2
Issue number3
DOIs
StatePublished - May 1 2017

Keywords

  • Hydrogen sulfide
  • Nitric oxide
  • Nitroxyl
  • Persulfide
  • Reactive nitrogen species
  • Reactive sulfur species
  • Transcriptomics

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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