Exploration of Human Skin Phageome to Reveal Endolysins and Novel Antimicrobial Peptides for Therapeutic Applications

The global rise of antibiotic-resistant pathogens has intensified the search for alternative therapeutics. Bacteriophage-derived endolysins are emerging as promising candidates. They exhibit strong potential due to their target specificity, rapid bactericidal action, and low tendency to induce bacterial resistance. This study presents a comprehensive metagenomic analysis of the human skin phageome using 1564 samples from 10 metagenomic projects. Our analysis led to the classification of 696 phage genomes into clusters and singletons. These genomes displayed considerable variation in size, GC content (average 56%), and coding efficiency (72%). A total of 968 endolysins were identified, including 75 SAR variants, with diverse domain architectures such as CHAP, Amidase, and SH3, suggesting host-specific adaptations. Notably, we identified 37 previously unreported endolysin-derived antimicrobial peptides (AMPs), several of which exhibited nontoxic, antifungal, and antiviral properties. Molecular dynamics and docking studies revealed strong binding affinity and stability of peptides EP-464 and EP-519 to key virulence factors, including Staphylococcus epidermidis autolysin (PDB: 4EPC), beta-lactamase VIM-2 (PDB: 5O7N), and AHL synthase LasI (PDB: 1RO5). These interactions suggest potential for disrupting bacterial virulence, resistance mechanisms, and quorum sensing. This study provides the first large-scale functional characterization of the human skin phageome focused on therapeutic endolysins and their novel AMP derivatives, offering promising candidates for the development of next-generation antimicrobial agents. However, further experimental validation is essential to assess their clinical efficacy in treating skin-related infections.