The Staphylococcus aureus SrrAB Two-Component System Promotes Resistance to Nitrosative Stress and Hypoxia

   Staphylococcus aureus is both a commensal and a pathogen of the human host. Survival in the host environment requires resistance to host-derived nitric oxide (NO·). However,S. aureus lacks the NO·-sensing transcriptional regulator NsrR that is used by many bacteria to sense and respond to NO·. In this study, we show thatS. aureus is able to sense and respond to both NO· and hypoxia by means of the SrrAB two-component system (TCS). Analysis of theS. aureus transcriptome during nitrosative stress demonstrates the expression of SrrAB-dependent genes required for cytochrome biosynthesis and assembly (qoxABCD ,cydAB ,hemABCX ), anaerobic metabolism (pflAB ,adhE ,nrdDG ), iron-sulfur cluster repair (scdA ), and NO· detoxification (hmp ). Targeted mutations in SrrAB-regulated loci show thathmp andqoxABCD are required for NO· resistance, whereasnrdDG is specifically required for anaerobic growth. We also show that SrrAB is required for survival in static biofilms, most likely due to oxygen limitation. Activation by hypoxia, NO·, or aqoxABCD quinol oxidase mutation suggests that the SrrAB TCS senses impaired electron flow in the electron transport chain rather than directly interacting with NO· in the manner of NsrR. Nevertheless, like NsrR, SrrAB achieves the physiological goals of selectively expressinghmp in the presence of NO· and minimizing the potential for Fenton chemistry. Activation of the SrrAB regulon allowsS. aureus to maintain energy production and essential biosynthetic processes, repair damage, and detoxify NO· in diverse host environments.IMPORTANCE The Hmp flavohemoglobin is required for nitric oxide resistance and is widely distributed in bacteria. Hmp expression must be tightly regulated, because expression under aerobic conditions in the absence of nitric oxide can exacerbate oxidative stress. In most organisms,hmp expression is controlled by the Fe-S cluster-containing repressor NsrR, but this transcriptional regulator is absent in the human pathogenStaphylococcus aureus . We show here thatS. aureus achieveshmp regulation in response to nitric oxide and oxygen limitation by placing it under the control of the SrrAB two-component system, which senses reduced electron flow through the respiratory chain. This provides a striking example of convergent evolution, in which the common physiological goals of responding to nitrosative stress while minimizing Fenton chemistry are achieved by distinct regulatory mechanisms.