ComK2 represses competence development for natural transformation in Staphylococcus aureus grown under strong oxygen limitation

The facultative anaerobe and major human pathogen Staphylococcus aureus is able to sustain growth under a wide range of oxygen concentrations. Importantly, we have already demonstrated that under microaerobic conditions, sensed by the two-component system SrrAB, S. aureus efficiently induces the development of competence for natural transformation, one of the three main horizontal gene transfer mechanisms present in bacteria. Here, we show that when the oxygen concentration decreases even further (reaching almost anaerobic conditions) the development of competence for natural transformation is still allowed but with much less efficiency than under microaerobic conditions. This inhibition is controlled by a central competence regulator, named ComK2, that was not found involved under intermediate oxygen concentrations. This ComK2-dependent inhibitory pathway also involves the SA2107 protein, of unknown function, through a direct protein-protein interaction. Finally, we demonstrate that this inhibition of competence is controlled by this strong oxygen limitation, sensed by another two-component system named NreBC, probably involved in the same pathway as ComK2 and SA2107. All in all, our results show that the oxygen concentration, which varies drastically depending on the site in the human body but also during bacterial infections, is a key environmental factor that tightly modulates S. aureus genomic plasticity.