Kowalski Caitlin H, Nguyen Uyen Thy, Lawhorn Susannah, Smith T Jarrod, Corrigan Rebecca M, Suh Won Se, Kalan Lindsay, Barber Matthew F
Institute of Ecology and Evolution, University of Oregon, Eugene, OR 97403, USA.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Microbiology Doctoral Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
Curr Biol. 2025 May 19;35(10):2266-2281.e8. doi: 10.1016/j.cub.2025.03.055. Epub 2025 Apr 14.
Microbiota promote host health by inhibiting pathogen colonization, yet how host-resident fungi or mycobiota contribute to this process remains unclear. The human skin mycobiota is uniquely stable compared with other body sites and dominated by skin-adapted yeasts of the genus Malassezia. We observe that colonization of human skin by Malassezia sympodialis significantly reduces subsequent colonization by the prominent bacterial pathogen Staphylococcus aureus. In vitro, M. sympodialis generates a hydroxyl palmitic acid isomer from environmental sources that has potent bactericidal activity against S. aureus in the context of skin-relevant stressors and is sufficient to impair S. aureus skin colonization. Leveraging experimental evolution to pinpoint mechanisms of S. aureus adaptation in response to antagonism by Malassezia, we identified multiple mutations in the stringent response regulator Rel that promote survival against M. sympodialis and provide a competitive advantage on human skin when M. sympodialis is present. Similar Rel alleles have been reported in S. aureus clinical isolates, and natural Rel variants are sufficient for tolerance to M. sympodialis antagonism. Partial stringent response activation underlies tolerance to clinical antibiotics, with both laboratory-evolved and natural Rel variants conferring multidrug tolerance in a manner that is dependent on the alternative sigma factor SigB. These findings demonstrate the ability of the mycobiota to mediate pathogen colonization resistance through generation of a hydroxy palmitic acid isomer, identify new mechanisms of bacterial adaptation in response to microbiota antagonism, and reveal the potential for microbiota-driven evolution to shape pathogen antibiotic susceptibility.
微生物群通过抑制病原体定殖来促进宿主健康，然而宿主固有真菌或真菌群如何促成这一过程仍不清楚。与身体其他部位相比，人类皮肤真菌群具有独特的稳定性，并且以马拉色菌属适应皮肤的酵母为主导。我们观察到，合轴马拉色菌在人类皮肤的定殖显著减少了随后主要细菌病原体金黄色葡萄球菌的定殖。在体外，合轴马拉色菌从环境来源生成一种羟基棕榈酸异构体，在与皮肤相关的应激源背景下，该异构体对金黄色葡萄球菌具有强大的杀菌活性，并且足以损害金黄色葡萄球菌在皮肤上的定殖。利用实验进化来确定金黄色葡萄球菌在应对马拉色菌拮抗作用时的适应机制，我们在严格反应调节因子Rel中鉴定出多个突变，这些突变可促进对合轴马拉色菌的存活，并在存在合轴马拉色菌时在人类皮肤上提供竞争优势。在金黄色葡萄球菌临床分离株中已报道了类似的Rel等位基因，天然Rel变体足以耐受合轴马拉色菌的拮抗作用。部分严格反应激活是对临床抗生素耐受性的基础，实验室进化的Rel变体和天然Rel变体均以依赖于替代sigma因子SigB的方式赋予多药耐受性。这些发现证明了真菌群通过生成羟基棕榈酸异构体来介导病原体定殖抗性的能力，确定了细菌在应对微生物群拮抗作用时适应的新机制，并揭示了微生物群驱动的进化塑造病原体抗生素敏感性的潜力。
