Adaptation to skin mycobiota promotes antibiotic tolerance inStaphylococcus aureus

Abstract

The microbiota can promote host health by inhibiting pathogen colonization, yet how host-resident fungi, or the mycobiota, contribute to this process remains unclear. The human skin mycobiota is uniquely stable compared to other body sites and dominated by yeasts of the genusMalassezia. We observe that colonization of human skin byMalassezia sympodialissignificantly reduces subsequent colonization by the prominent bacterial pathogenStaphylococcus aureus.M. sympodialissecreted products possess potent bactericidal activity againstS. aureusand are sufficient to impairS. aureusskin colonization. This bactericidal activity requires an acidic environment and is exacerbated by free fatty acids, demonstrating a unique synergy with host-derived epidermal defenses. Leveraging experimental evolution to pinpoint mechanisms ofS. aureusadaptation in response to the skin mycobiota, we identified multiple mutations in the stringent response regulator Rel that promote survival againstM. sympodialis. Similar Rel alleles have been reported inS. aureusclinical isolates, and natural Rel variants are sufficient for tolerance toM. sympodialisantagonism. Partial stringent response activation underlies tolerance to clinical antibiotics, with both laboratory-evolved and natural Rel variants conferring multidrug tolerance. These findings demonstrate the ability of the mycobiota to mediate pathogen colonization resistance, identify new mechanisms of bacterial adaptation in response to fungal antagonism, and reveal the potential for microbiota-driven evolution to shape pathogen antibiotic susceptibility.