Adaptation to skin mycobiota promotes antibiotic tolerance in .

Unlabelled: 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 genus . We observe that colonization of human skin by significantly reduces subsequent colonization by the prominent bacterial pathogen . secreted products possess potent bactericidal activity against and are sufficient to impair skin 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 of adaptation in response to the skin mycobiota, we identified multiple mutations in the stringent response regulator Rel that promote survival against . Similar Rel alleles have been reported in clinical isolates, and natural Rel variants are sufficient for tolerance to antagonism. 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.

Highlights: - reduces colonization of human skin by - Bactericidal activity of is exacerbated by features of the skin niche - Rel variants are sufficient for tolerance to antagonism - Evolved tolerance to yeast antagonism coincides with multidrug tolerance.