Staphylococcus aureus PerR is a hypersensitive hydrogen peroxide sensor using fe-mediated histidine oxidation

In many Gram positive bacteria PerR is a major peroxide sensor whose repressor activity is dependent on a bound metal cofactor. The prototype for PerR sensors, the Bacillus subtilis PerRBS protein, represses target genes when bound to either Mn2+ or Fe2+ as corepressor, but only the Fe2+-bound form responds to H2O2. The orthologous protein in the human pathogen Staphylococcus aureus, PerRSA, plays important roles in H2O2 resistance and virulence. However, PerRSA is reported to only respond to Mn2+ as corepressor, which suggests that it might rely on a distinct, iron-independent mechanism for H2O2 sensing. Here we demonstrate that PerRSA uses either Fe2+ or Mn2+ as corepressor, and that, like PerRBS, the Fe2+-bound form of PerRSA senses physiological levels of H2O2 by Fe-mediated histidine oxidation. Moreover, we show that PerRSA is poised to sense very low levels of endogenous H2O2 which normally cannot be sensed by B. subtilis PerRBS. This hypersensitivity of PerRSA accounts for the apparent lack of Fe2+-dependent repressor activity and consequent Mn2+-specific repressor activity under aerobic conditions. We also provide evidence that the activity of PerRSA is directly correlated with virulence, whereas it is inversely correlated with H2O2 resistance, suggesting that PerRSA may be an attractive target for the control of S. aureus pathogenesis.