Selective Depletion of Staphylococcus aureus Restores the Skin Microbiome and Accelerates Tissue Repair after Injury

Wilkinson, Holly N.; Stafford, Amber R.; Rudden, Michelle; Rocha, Nina D.C.; Kidd, Alexandria S.; Iveson, Sammi; Bell, Andrea L.; Hart, Jeffrey; Duarte, Ana; Frieling, Johan; Janssen, Ferd; Röhrig, Christian; de Rooij, Bob; Ekhart, Peter F.; Hardman, Matthew J.

Abstract

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.

Citation

Wilkinson, H. N., Stafford, A. R., Rudden, M., Rocha, N. D., Kidd, A. S., Iveson, S., Bell, A. L., Hart, J., Duarte, A., Frieling, J., Janssen, F., Röhrig, C., de Rooij, B., Ekhart, P. F., & Hardman, M. J. (2024). Selective Depletion of Staphylococcus aureus Restores the Skin Microbiome and Accelerates Tissue Repair after Injury. Journal of Investigative Dermatology, 144(8), 1865-1876. https://doi.org/10.1016/j.jid.2024.01.018

• Journal Article Type: Article
• Acceptance Date: Jan 16, 2024
• Online Publication Date: Feb 1, 2024
• Publication Date: Aug 1, 2024
• Deposit Date: Feb 28, 2024
• Publicly Available Date: Jul 23, 2024
• Journal: Journal of Investigative Dermatology
• Print ISSN: 0022-202x
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 144
• Issue: 8
• Pages: 1865-1876
• DOI: https://doi.org/10.1016/j.jid.2024.01.018
• Keywords: Endolysin; Infection; Microbiome; Skin; Wound healing
• Public URL: https://hull-repository.worktribe.com/output/4565883