|SUJATA CHAUDHARI, PhD
BS, University of Pune
Staphylococcus aureus is the primary etiological agent of human skin and soft tissue infections (SSTI). We are interested in understanding how unregulated cysteine/cystine uptake may adversely impact staphylococcal growth during skin abscess formation. Cysteine, a sulfur-containing amino acid is important for multiple physiological processes. During infection in addition to a carbon source, S. aureus would require a source of sulfur to persist within the abscess. Most bacteria can channel sulfates and sulfites to a central intracellular pool of cysteine from which all sulfur-containing biomolecules are derived. However, S. aureus does not have metabolic pathways that utilize sulfates/ sulfites from the environment. Rather, it depends on the direct uptake of cystine to satisfy its sulfur needs. This approach by the cell presents itself a unique problem. Free cystine is usually toxic to cells. Thus, it must rapidly be reduced to cysteine upon entry into the cytoplasm. However, due to the high reactivity of the cysteinyl thiol groups with cytoplasmic metals like free iron (Fe3+), it can be re-oxidized to cystine and in the process, potentially, feed into the Fenton chemistry to generate harmful hydroxyl radicals. This process is aggravated when thiol-reactive compounds further disbalance the cysteine-cystine redox cycle. The underlying cause of cystine cytotoxicity and the mechanisms that S. aureus employ to regulate intracellular cystine concentrations are the subjects of our investigation. Additionally, we investigate the relationship between regulation of intracellular cystine pools and S. aureus pathogenesis.
Bosch ME, Bertrand BP, Heim CE, Alqarzaee AA, Chaudhari SS, Aldrich AL, Fey PD, Thomas VC, Kielian T. Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity. mBio. 2020 Sep 8;11(5):e01581-20.
Heim CE, Bosch ME, Yamada KJ, Aldrich AL, Chaudhari SS, Klinkebiel D, Gries CM, Alqarzaee AA, Li Y, Thomas VC, Seto E, Karpf AR, Kielian T. Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection. Nat Microbiol. 2020 Oct;5(10):1271-1284.
Zhou C, Bhinderwala F, Lehman MK, Thomas VC, Chaudhari SS, Yamada KJ, Foster KW, Powers R, Kielian T, Fey PD. Urease is an essential component of the acid response network of Staphylococcus aureus and is required for a persistent murine kidney infection. PLoS Pathog. 2019 Jan 4;15(1):e1007538.
Chaudhari SS, Kim M, Lei S, Razvi F, Alqarzaee AA, Hutfless EH, Powers R, Zimmerman MC, Fey PD, Thomas VC. Nitrite Derived from Endogenous Bacterial Nitric Oxide Synthase Activity Promotes Aerobic Respiration. mBio. 2017 Aug 1;8(4):e00887-17.
Chaudhari SS, Thomas VC, Sadykov MR, Bose JL, Ahn DJ, Zimmerman MC, Bayles The LysR-type transcriptional regulator, CidR, regulates stationary phasecell death in Staphylococcus aureus. Mol Microbiol. 2016 Sep;101(6):942-53.
Gries CM, Sadykov MR, Bulock LL, Chaudhari SS, Thomas VC, Bose JL, Bayles KW. Potassium Uptake Modulates Staphylococcus aureus Metabolism. mSphere. 2016 Jun 15;1(3):e00125-16.
Windham IH, Chaudhari SS, Bose JL, Thomas VC, Bayles KW. SrrAB Modulates Staphylococcus aureus Cell Death through Regulation of cidABC Transcription. J Bacteriol. 2016 Jan 25;198(7):1114-22.
Thomas VC, Chaudhari SS, Jones J, Zimmerman MC, Bayles KW. Electron Paramagnetic Resonance (EPR) Spectroscopy to Detect Reactive Oxygen Species in Staphylococcus aureus. Bio Protoc. 2015 Sep 5;5(17):e1586.
Thomas VC, Sadykov MR, Chaudhari SS, Jones J, Endres JL, Widhelm TJ, Ahn JS, Jawa RS, Zimmerman MC, Bayles KW. A central role for carbon-overflow pathways in the modulation of bacterial cell death. PLoS Pathog. 2014 Jun 19;10(6):e1004205.
Lindgren JK, Thomas VC, Olson ME, Chaudhari SS, Nuxoll AS, Schaeffer CR, Lindgren KE, Jones J, Zimmerman MC, Dunman PM, Bayles KW, Fey PD. Arginine deiminase in Staphylococcus epidermidis functions to augment biofilm maturation through pH homeostasis. J Bacteriol. 2014 Jun;196(12):2277-89.
Thomas VC, Kinkead LC, Janssen A, Schaeffer CR, Woods KM, Lindgren JK, Peaster JM, Chaudhari SS, Sadykov M, Jones J, AbdelGhani SM, Zimmerman MC, Bayles KW, Somerville GA, Fey PD. A dysfunctional tricarboxylic acid cycle enhances fitness of Staphylococcus epidermidis during β-lactam stress. mBio. 2013 Aug 20;4(4):e00437-13. doi: 10.1128/mBio.00437-13. Erratum in: MBio. 2014;5(3):e01307-14. Chittezham Thomas, Vinai [corrected to Thomas, Vinai C].