Specialized phosphate transport is essential for Staphylococcus aureus nitric oxide resistance.

Staphylococcus aureus is a major human pathogen capable of causing a variety of diseases ranging from skin and soft tissue infections to systemic presentations such as sepsis, endocarditis, and osteomyelitis. For S. aureus to persist as a pathogen in these environments, it must be able to resist the host immune response, including the production of reactive oxygen and nitrogen species (e.g., nitric oxide, NO·). Extensive work from our lab has shown that S. aureus is highly resistant to NO·, especially in the presence of glucose. RNA-seq performed on S. aureus exposed to NO· in the presence and absence of glucose showed a new system important for NO· resistance-phosphate transport. The phosphate transport systems pstSCAB and nptA are both upregulated upon NO·-exposure, particularly in the presence of glucose. Both are key for phosphate transport at an alkaline pH, which the cytosol of S. aureus becomes under NO· stress. Accordingly, the Δ pstS Δ nptA mutant is attenuated under NO stress in vitro as well as in macrophage and murine infection models. This work defines a new role in infection for two phosphate transporters in S. aureus and provides insight into the complex system that is NO· resistance in S. aureus .IMPORTANCE Staphylococcus aureus is a bacterial pathogen capable of causing a wide variety of disease in humans. S. aureus is unique in its ability to resist the host immune response, including the antibacterial compound known as nitric oxide (NO·). We used an RNA-sequencing approach to better understand the impact of NO· on S. aureus in different environments. We discovered that inorganic phosphate transport is induced by the presence of NO·. Phosphate is important for the generation of energy from glucose, a carbon source favored by S. aureus . We show that the absence of these phosphate transporters causes lowered energy levels in S. aureus . We find that these phosphate transporters are essential for S. aureus to grow in the presence of NO· and to cause infection. Our work here contributes significantly to our understanding of S. aureus NO· resistance and provides a new context in which S. aureus phosphate transporters are essential.