Nitrite derived from endogenous bacterial nitric oxide synthase activity promotes aerobic respiration

: Macrophage-derived nitric oxide (NO·) is a crucial effector against invading pathogens. Yet, paradoxically, several bacterial species, including some pathogens, are known to endogenously produce NO· via nitric oxide synthase (NOS) activity, despite its apparent cytotoxicity. Here, we reveal a conserved role for bacterial NOS in activating aerobic respiration. We demonstrate that nitrite generated from endogenous NO· decomposition stimulates quinol oxidase activity in Staphylococcus aureus and increases the rate of cellular respiration. This not only supports optimal growth of this organism but also prevents a dysbalance in central metabolism. Further, we also show that activity of the SrrAB two-component system alleviates the physiological defects of the nos mutant. Our findings suggest that NOS and SrrAB constitute two distinct but functionally redundant routes for controlling staphylococcal respiration during aerobic growth.IMPORTANCE Despite its potential autotoxic effects, several bacterial species, including pathogenic staphylococcal species, produce NO· endogenously through nitric oxide synthase (NOS) activity. Therefore, how endogenous NO· influences bacterial fitness remains unclear. Here we show that the oxidation of NO· to nitrite increases aerobic respiration and consequently optimizes central metabolism to favor growth. Importantly, we also demonstrate that cells have a "fail-safe" mechanism that can maintain respiratory activity through the SrrAB two-component signaling regulon should NOS-derived nitrite levels decrease. These findings identify NOS and SrrAB as critical determinants of staphylococcal respiratory control and highlight their potential as therapeutic targets.