The Staphylococcus aureus SrrAB Regulatory System Modulates Hydrogen Peroxide Resistance Factors, Which Imparts Protection to Aconitase during Aerobic Growth

The SrrAB two-component regulatory system (TCRS) positively influences the transcription of genes involved in aerobic respiration in response to changes in respiratory flux. Hydrogen peroxide (H(2)O(2)) can arise as a byproduct of spontaneous interactions between dioxygen and components of respiratory pathways. H(2)O(2) damages cellular factors including protein associated iron-sulfur cluster prosthetic groups. We found that a Staphylococcus aureus strain lacking the SrrAB two-component regulatory system (TCRS) is sensitive to H(2)O(2) intoxication. We tested the hypothesis that SrrAB manages the mutually inclusive expression of genes required for aerobic respiration and H(2)O(2) resistance. Consistent with our hypothesis, a ΔsrrAB strain had decreased transcription of genes encoding for H(2)O(2) resistance factors (kat, ahpC, dps). SrrAB was not required for the inducing the transcription of these genes in cells challenged with H(2)O(2). Purified SrrA bound to the promoter region for dps suggesting that SrrA directly influences dps transcription. The H(2)O(2) sensitivity of the ΔsrrAB strain was alleviated by iron chelation or deletion of the gene encoding for the peroxide regulon repressor (PerR). The positive influence of SrrAB upon H(2)O(2) metabolism bestowed protection upon the solvent accessible iron-sulfur (FeS) cluster of aconitase from H(2)O(2) poisoning. SrrAB also positively influenced transcription of scdA (ytfE), which encodes for a FeS cluster repair protein. Finally, we found that SrrAB positively influences H(2)O(2) resistance only during periods of high dioxygen-dependent respiratory activity. SrrAB did not influence H(2)O(2) resistance when cellular respiration was diminished as a result of decreased dioxygen availability, and negatively influenced it in the absence of respiration (fermentative growth). We propose a model whereby SrrAB-dependent regulatory patterns facilitate the adaptation of cells to changes in dioxygen concentrations, and thereby aids in the prevention of H(2)O(2) intoxication during respiratory growth upon dixoygen.