Persulfide sensing and Reactive Sulfur Species in Bacterial Pathogens

Persulfide Sensing and Reactive Sulfur Species (RSS) in Bacteria

In this project, we are developing new concepts of bacterial hydrogen sulfide (H2S) homeostasis, and seeking an understanding of the chemistry and physiological adaptation of H2S misregulation in important microbial pathogens.  In 2014, we discovered a paralog of a copper-sensing operon repressor CsoR in Staphylococcus 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 in selected firmicutes and in Gram-negative bacteria (Rhodobacter, Acinetobacter spp.) reveals that RSS sensing and hydrogen sulfide homeostasis is clearly more widespread than previously thought.

Our biochemical studies reveal that the cst operon in S. aureus encodes a nearly complete mitochondrial-like sulfide oxidation system (S2- to thiosulfate, S2O32-), the core determinants of which are duplicated in methicillin-resistant S. aureus (MRSA). Ongoing studies seek to understand cellular metabolic adaptation to sulfide misregulation, with a particular interest in global profiling of protein S-sulfuration (S-sulfhydration; persulfidation) in myriad bacterial cells using a combination of microbiological, biochemical and chemical biology approaches in an effort to identify common features. We are also exploring how a potential interplay of RSS and reactive nitrogen species (RNS) impacts this adaptive response.

Reviews and Perspectives


Structural basis for persulfide-sensing specificity in a transcriptional regulator
Capdevila, D. A., Walsh, B. J. C., Zhang, Y., Dietrich, C., Gonzalez-Gutierrez, G., and GIEDROC, D. P. (2020)
Nat. Chem. Biol., in the press (doi: 10.1038/s41589-020-00671-9)
View: PubMed

Staphylococcus aureus glucose-induced biofilm accessory protein A (GbaA) is a monothiol-dependent electrophile sensor
Ray, A., Edmonds, K. A., Palmer, L. D., Skaar, E. P., and GIEDROC, D. P. (2020)
Biochemistry 59, 2882–2895 (doi: 10.1021/acs.biochem.0c00347).
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The response of Acinetobacter baumannii to hydrogen sulfide reveals two independent persulfide-sensing systems and a connection to biofilm regulation
Walsh, B.J.C., Wang, J., Edmonds, K. A., Palmer, L. D., Zhang, Y., Trinidad, J. C., Skaar, E. P., and GIEDROC, D. P. (2020)
mBio 11, e01254-20 (doi: 10.1128/mBio.01254-20).
View: PubMed

Thioredoxin profiling of multiple thioredoxin-like proteins in Staphylococcus aureus
Peng, H., Zhang, Y., Trinidad, J. C.,  & Giedroc, D. P. (2018)
Front. Microbiol. 9, 2385  (doi: 10.3389/fmicb.2018.02385)
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Hydrogen sulfide sensing through reactive sulfur species (RSS) and nitroxyl (HNO) in Enterococcus faecalis
Shen, J., Walsh, B. J. C., Flores-Mireles, A. L., Peng, H., Zhang, Y., Zhang, Y., Trinidad, J. C., Hultgren, S. J., & Giedroc, D. P. (2018)
ACS Chem. Biol. 13, 1610-1620 (doi: 10.1021/acschembio.8b00230)
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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).
View: PubMed

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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H2S and reactive sulfur signaling at the host bacterial pathogen interface
Walsh, B. J. C. and GIEDROC, D. P. (2020)
J. Biol. Chem. 295, 13150-13168  (doi: 10.1074/jbc.REV120.011304)
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Hydrogen sulfide signaling and enzymology
In Comprehensive Natural Products III: Chemistry and Biology, Vol 4, pp. 430–473 (Liu, H.-W., Begley, T., eds.)
Walsh, B. J. C., Brito, J. A., and GIEDROC, D. P. (2020)
Elsevier, Ltd., Oxford, UK
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A new player in bacterial sulfide-inducible transcriptional regulation
GIEDROC, D. P. (2017)
Mol. Microbiol. 105, 347-352 (doi: 10.1111/mmi.13726)
View: PubMed

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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