Sulfide Homeostasis and Nitroxyl Intersect via Formation of Reactive Sulfur Species in Staphylococcus aureus

Abstract

Hydrogen sulfide (H2S) is a toxic molecule and a recently described gasotransmitter in vertebrates whose function in bacteria is not well understood. In this work, we describe the transcriptomic response of the major human pathogen Staphylococcus aureus to quantified changes in levels of cellular organic reactive sulfur species, which are effector molecules involved in H2S signaling. We show that nitroxyl (HNO), a recently described signaling intermediate proposed to originate from the interplay of H2S and nitric oxide, also induces changes in cellular sulfur speciation and transition metal homeostasis, thus linking sulfide homeostasis to an adaptive response to antimicrobial reactive nitrogen species.

Hydrogen Sulfide and Reactive Sulfur Species Impact Proteome S-Sulfhydration and Global Virulence Regulation in Staphylococcus aureus

“…20,24 Here, we show that these RSS levels can be affected by genetic background and growth conditions. The concentration of the major reducing LMW thiol, bacillithiol (BSH), is in the ≈3 mM range, as expected, 30 with the concentration of coenzyme A (CoASH) and cysteine (CysSH) comparable and ≈3-fold lower, respectively, relative to BSH (Table S1).…”

“…These data are consistent with the reactivity of H 2 S toward H 2 O 2 , a protective effect of organic RSS against ROS stress, and generally opposite transcriptomic profiles associated with RSS and ROS in S. aureus . 5,18,24 In any case, the quantitation of cellular RSS reveals that key inorganic and organic H 2 S signaling molecules can be controlled endogenously by genetic background or by addition of exogenous sulfide. This allows us to test the impact of perturbation of RSS on specific metabolic and regulatory processes.…”

“…21–23 These regulators sense RSS directly, which can be detected and quantified in bacterial cells. 20,24 However, little is known about what role H 2 S and downstream RSS play in cellular sulfur speciation and if H 2 S signaling impacts S. aureus pathogenesis and other biological processes. Sulfur metabolism is generally important for bacterial pathophysiology, and targeting microbial sulfur assimilation is a validated approach for the development of new antimicrobial agents.…”

“…7,8 Endogenous biogenesis of H 2 S occurs in S. aureus , and the concentrations of sulfide and downstream inorganic and organic RSS can be controlled via genetic or chemical perturbation of endogenous or exogenous sulfide levels. 24 H 2 S is produced primarily by the enzymes of the transsulfuration pathway, 28 cystathionine- β -synthase (CBS, encoded by cysM ) and cystathionine- γ -lyase (CSE, metB ). A dithiol-containing repressor of the cst operon, CstR, for CsoR-like sulfurtransferase repressor, 29 regulates the transcription of a sulfide oxidation system that is partly used to clear excess sulfide in S. aureus strain Newman.…”

“…A dithiol-containing repressor of the cst operon, CstR, for CsoR-like sulfurtransferase repressor, 29 regulates the transcription of a sulfide oxidation system that is partly used to clear excess sulfide in S. aureus strain Newman. 24 …”