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

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.

Breathing new life into old antibiotics: overcoming antibacterial resistance by antibiotic-loaded nanogel carriers with cationic surface functionality.

Multidrug-resistant pathogens are prevalent in chronic wounds. There is an urgent need to develop novel antimicrobials and formulation strategies that can overcome antibiotic resistance and provide a safe alternative to traditional antibiotics. This work aimed to develop a novel nanocarrier for two cationic antibiotics, tetracycline hydrochloride and lincomycin hydrochloride which can potentially overcome antibiotic resistance. In this study, we report the use of surface functionalised polyacrylic copolymer nanogels as carriers for cationic antibiotics. These nanogels can encapsulate small cationic antimicrobial molecules and act as a drug delivery system. They were further functionalised with a biocompatible cationic polyelectrolyte, bPEI, to increase their affinity towards the negatively charged bacterial cell walls. These bPEI-coated nanocarrier-encapsulated antibiotics were assessed against a range of wound isolated pathogens, which had been shown through antimicrobial susceptibility testing (AST) to be resistant to tetracycline and lincomycin. Our data reveal that bPEI-coated nanogels with encapsulated tetracycline or lincomycin displayed increased antimicrobial performance against selected wound-derived bacteria, including strains highly resistant to the free antibiotic in solution. Additionally, our nanocarrier-based antibiotics showed no detectable cytotoxic effect against human keratinocytes. We attribute the increase in the antimicrobial activity of the cationically functionalised antibiotic-loaded nanogel carriers to specific electrostatic adhesion to the microbial cell wall delivering a higher local antibiotic concentration, confirmed by scanning electron microscopy. Such a nanotechnology based approach may enhance the effectiveness of a wide variety of existing antibiotics, offering a potentially new mechanism to overcome antibiotic resistance.

A Novel Silver Bioactive Glass Elicits Antimicrobial Efficacy Against Pseudomonas aeruginosa and Staphylococcus aureus in an ex Vivo Skin Wound Biofilm Model.

Biofilm infection is now understood to be a potent contributor to the recalcitrant nature of chronic wounds. Bacterial biofilms evade the host immune response and show increased resistance to antibiotics. Along with improvements in antibiotic stewardship, effective new anti-biofilm therapies are urgently needed for effective wound management. Previous studies have shown that bioactive glass (Bg) is able to promote healing with moderate bactericidal activity. Here we tested the antimicrobial efficacy of a novel BG incorporating silver (BgAg), against both planktonic and biofilm forms of the wound-relevant bacteria Pseudomonas aeruginosa and Staphylococcus aureus. BgAg was stable, long lasting, and potently effective against planktonic bacteria in time-kill assays (6-log reduction in bacterial viability within 2 h) and in agar diffusion assays. BgAg reduced bacterial load in a physiologically relevant ex vivo porcine wound biofilm model; P. aeruginosa (2-log reduction) and S. aureus (3-log reduction). BgAg also conferred strong effects against P. aeruginosa biofilm virulence, reducing both protease activity and virulence gene expression. Co-culture biofilms appeared more resistant to BgAg, where a selective reduction in S. aureus was observed. Finally, BgAg was shown to benefit the host response to biofilm infection, directly reducing host tissue cell death. Taken together, the findings provide evidence that BgAg elicits potent antimicrobial effects against planktonic and single-species biofilms, with beneficial effects on the host tissue response. Further investigations are required to elucidate the specific consequences of BG administration on polymicrobial biofilms, and further explore the effects on host-microbe interactions.