An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization

Nitric oxide (NO^•) is a ubiquitous molecular mediator in biology. Many signalling actions of NO^• generated by mammalian NO^• synthase (NOS) result from targeting of the haem moiety of soluble guanylate cyclase. Some pathogenic and environmental bacteria also produce a NOS that is evolutionary related to the mammalian enzymes, but a bacterial haem-containing receptor for endogenous enzymatically generated NO^• has not been identified previously. Here, we show that NOS of the human pathogen Staphylococcus aureus, in concert with an NO^•-metabolizing flavohaemoprotein, regulates electron transfer by targeting haem-containing cytochrome oxidases under microaerobic conditions to maintain membrane bioenergetics. This process is essential for staphylococcal nasal colonization and resistance to the membrane-targeting antibiotic daptomycin and demonstrates the conservation of NOS-derived NO^•-haem receptor signalling between bacteria and mammals.