Biomedical Institute for Multimorbidity, Centre for Biomedicine, Hull York Medical School, The University of Hull, Hull, United Kingdom; Skin Research Centre, Hull York Medical School, The University of York, Heslington, United Kingdom.
Biomedical Institute for Multimorbidity, Centre for Biomedicine, Hull York Medical School, The University of Hull, Hull, United Kingdom.
J Invest Dermatol. 2024 Aug;144(8):1865-1876.e3. doi: 10.1016/j.jid.2024.01.018. Epub 2024 Feb 1.
Our skin is home to a diverse community of commensal microorganisms integral to cutaneous function. However, microbial dysbiosis and barrier perturbation increase the risk of local and systemic infection. Staphylococcus aureus is a particularly problematic bacterial pathogen, with high levels of antimicrobial resistance and direct association with poor healing outcome. Innovative approaches are needed to selectively kill skin pathogens, such as S aureus, without harming the resident microbiota. In this study, we provide important data on the selectivity and efficacy of an S aureus-targeted endolysin (XZ.700) within the complex living skin/wound microbiome. Initial cross-species comparison using Nanopore long-read sequencing identified the translational potential of porcine rather than murine skin for human-relevant microbiome studies. We therefore performed an interventional study in pigs to assess the impact of endolysin administration on the microbiome. XZ.700 selectively inhibited endogenous porcine S aureus in vivo, restoring microbial diversity and promoting multiple aspects of wound repair. Subsequent mechanistic studies confirmed the importance of this microbiome modulation for effective healing in human skin. Taken together, these findings strongly support further development of S aureus-targeted endolysins for future clinical management of skin and wound infections.
我们的皮肤是共生微生物的家园，这些微生物对皮肤功能至关重要。然而，微生物失调和屏障破坏会增加局部和全身感染的风险。金黄色葡萄球菌是一种特别成问题的细菌病原体，具有高水平的抗药性，并直接与不良的愈合结果相关。需要创新的方法来选择性地杀死皮肤病原体，如金黄色葡萄球菌，而不伤害常驻微生物群。在这项研究中，我们提供了关于一种针对金黄色葡萄球菌的内切酶（XZ.700）在复杂的活体皮肤/伤口微生物群中的选择性和功效的重要数据。使用纳米孔长读测序进行的初始跨物种比较确定了猪皮而不是鼠皮更适合用于人类相关微生物组研究。因此，我们在猪中进行了一项干预研究，以评估内切酶给药对微生物组的影响。XZ.700 选择性地抑制了体内的内源性猪金黄色葡萄球菌，恢复了微生物多样性，并促进了伤口修复的多个方面。随后的机制研究证实了这种微生物组调节对于人类皮肤有效愈合的重要性。总之，这些发现强烈支持进一步开发针对金黄色葡萄球菌的内切酶，以用于未来皮肤和伤口感染的临床管理。
