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- 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- targeted endolysins for future clinical management of skin and wound infections.

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. Here 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.

Objective: Traditional negative pressure wound therapy (tNPWT) systems can be large and cumbersome, limiting patient mobility and adversely affecting quality of life. PICO™, a no canister single-use system, offers a lightweight, portable alternative to tNPWT, with improved clinical performance. The aim of this study was to determine the potential mechanism(s) of action of single-use NPWT (sNPWT) versus tNPWT. Approach: sNPWT and tNPWT were applied to an in vivo porcine excisional wound model, following product use guidelines. Macroscopic, histological, and biochemical analyses were performed at defined healing time points to assess multiple aspects of the healing response. Results: Wounds treated with single-use negative pressure displayed greater wound closure and increased reepithelialization versus those treated with traditional negative pressure. The resulting granulation tissue was more advanced with fewer neutrophils, reduced inflammatory markers, more mature collagen, and no wound filler-associated foreign body reactions. Of note, single-use negative pressure therapy failed to induce wound edge epithelial hyperproliferation, while traditional negative pressure therapy compromised periwound skin, which remained inflamed with high transepidermal water loss; features not observed following single-use treatment. Innovation: Single-use negative pressure was identified to improve multiple aspects of healing versus traditional negative pressure treatment. Conclusion: This study provides important new insight into the differing mode of action of single-use versus traditional negative pressure and may go some way to explaining the improved clinical outcomes observed with single-use negative pressure therapy.