Sulfide sensing and Reactive Sulfur Species in Staphylococcus aureus

Sulfide Sensing and Reactive Sulfur Species (RSS) in Bacteria

Staphylococcus aureus is a major nosocomial pathogen and the causative agent of myriad severe hospital and community acquired infections. Recent work published by another group has reported that the ability of Staphylococcus aureus and other bacteria to mitigate the effects of stress induced by antibiotics is linked to increases in endogenous hydrogen sulfide (H2S) and nitric oxide (NO•). Our group discovered a paralog of a copper-sensing operon repressor CsoR in S. aureus that we coined CstR, for CsoR-like sulfurtransferase repressor. CstR senses reactive sulfur species (RSS), including inorganic and organic low molecular weight (LMW) thiol persulfides, that result from the effects of sulfide stress, resulting in induction of the cst operon. Ongoing work suggests that RSS sensing and hydrogen sulfide homeostasis is more widespread than previously anticipated.

Our biochemical studies reveal that the cst operon encodes a nearly complete mitochondrial-like sulfide oxidation system (S2- to thiosulfate, S2O3 2-), the core determinants of which are duplicated in metthicillin-resistant S. aureus(MRSA). We hypothesize that these enzymes may be required to clear LMW persulfides that accumulate under conditions of H2S up- or misregulation. Ongoing studies are directed toward probing the transcriptomic, metabolomic and proteomic response of S. aureus and a related Gram-positive pathogen Enterococcus faecalis (collaboratively with the Hultgren group, Washington University, St. Louis) to sulfide misregulation, with a particular interest in profiling of protein S-sulfhydration in cells. We are also exploring how a potential interplay of RSS and reactive nitrogen species (RNS) impacts this adaptive response and potentially, biofilm dynamics, of these important human pathogens.

Reviews and Perspectives


Hydrogen sulfide and reactive sulfur species impact S-sulfhydration and global virulence regulation in Staphylococcus aureus
Peng, H., Zhang, Y., Palmer, L, D., Kehl-Fie, T. E., Skaar, E. C., Trinidad, J. C., & Giedroc, D. P. (2017)
ACS Infect. Dis. 3, 744-755 (doi: 10.1021/acsinfecdis.7b00090)
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Sulfide homeostasis and nitroxyl intersect via formation of reactive sulfur species (RSS) in Staphylococcus aureus
Peng, H., Shen, J., Edmonds, K. A., Luebke, J. L., Hickey, A. K., Palmer, L, D., Cheng, F.-M.J., Bruce, K. A., Kehl-Fie, T. E., Skaar, E. C., & Giedroc, D. P. (2017)
mSphere 2e00082-17 (doi:10.1128/mSphere.00082-17) 
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The sulfide-responsive transcriptional repressor SqrR functions as a master regulator of sulfide-dependent photosynthesis
Shimizu, T., Shen, J., Fang, M., Zhang, Y., Hori, K., Trinidad, J. C., Bauer, C. E., Giedroc, D. P. and Masuda, S. (2017)
Proc. Natl. Acad. Sci. U.S.A. 114, 2355-2360 (doi: 10.1073/pnas.1614133114).
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Staphylococcus aureus sqr encodes a type II sulfide:quinone oxidoreductase (SQR) and impacts reactive sulfur speciation in cells
Shen, J., Peng, H., Zhang, Y., Trinidad, J. C., & Giedroc, D. P. (2016)
Biochemistry 55, 6524-6534
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Staphylococcus aureus CstB is a novel multidomain persulfide dioxygenase-sulfurtransferase involved in hydrogen sulfide detoxification
Shen, J., Keithly, M. E., Armstrong, R. N., Higgins, K. A., Edmonds, K. A. & Giedroc, D. P. (2015)
Biochemistry 54, 4542-4554 (doi: 10.1021/acs.biochem.5b00584)
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Conformational analysis and chemical reactivity of the multidomain sulfurtransferase, Staphylococcus aureus CstA
Higgins, K. A., Peng, H., Luebke, J. L., Chang, F.-M. J., & Giedroc, D. P. (2015)
Biochemistry 54, 2385-2398 (doi: 10.1021/acs.biochem.5b00056)
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The CsoR-like sulfurtransferase repressor (CstR) is a persulfide sensor in Staphylococcus aureus.
Luebke, J. L., Shen, J., Bruce, K. E., Kehl-Fie, T. E., Peng, H., Skaar, E. P., & Giedroc, D. P. (2014)
Mol. Microbiol. 94, 1343-1360 (doi: 10.1111/mmi.12835)
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Selenite and tellurite form mixed seleno- and tellurotrisulfides with CstR from Staphylococcus aureus
Luebke, J. L., Arnold, R. A. & Giedroc, D. P. (2013)
Metallomics 5, 335-342 (doi: 10.1039/c3mt20205d)
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Control of copper resistance and inorganic sulfur metabolism by paralogous regulators in Staphylococcus aureus
Grossoehme, N., Kehl-Fie, T.E., Ma, Z., Adams, K.W., Cowart, D.M., Scott, R.A., Skaar, E.P., & Giedroc, D.P. (2011)
J. Biol. Chem. 286, 13522-13531
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A new player in bacterial sulfide-inducible transcriptional regulation
Giedroc, D. P. (2017)
Mol. Microbiol, in the press (doi: 10.1111/mmi.13726)
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Cysteine sulfur chemistry in transcriptional regulators at the host-bacterial pathogen interface
Luebke, J. L., & Giedroc, D. P. (2015)
Biochemistry 54, 3235-3249 (doi: 10.1021/acs.biochem.5b00085)
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