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.