Large-scale investigation for antimicrobial activity reveals newly-identified defensive species across the healthy skin microbiome.

The skin microbiome forms a protective barrier to pathogens, including through the production of antimicrobial metabolites. Here, we present EPICHHS, a large and taxonomically diverse skin microbiome culture collection of 968 strains from eight body sites. EPICHHS captures >95% of cumulative species-level abundance across 268 skin metagenomes. It includes isolates present at <0.1% relative abundance and the cultured representatives for eight species not previously isolated, markedly expanding current skin microbiome resources. A contact-independent screen assaying ~14,000 pairwise interactions against 22 pathogens revealed widespread antagonism with striking enrichment for antifungal activity. Finally, functional genomic analysis, including 287 EPICHHS isolate genomes, demonstrated a diverse landscape of skin-associated biosynthetic gene clusters that are mostly uncharacterized. Together EPICHHS, its functional and genomic characterization, establishes the skin microbiome as a reservoir for specialized metabolism and provides a platform for microbiome-based antimicrobial discovery.