Harnessing diversity and antagonism within the pig skin microbiota to identify novel mediators of colonization resistance to methicillin-resistant Staphylococcus aureus

The microbiota mediates multiple aspects of skin barrier function, including colonization resistance to pathogens such as Staphylococcus aureus. The endogenous skin microbiota limits S. aureus colonization via competition and direct inhibition. Novel mechanisms of colonization resistance are promising therapeutic targets for drug-resistant infections, such as those caused by methicillin-resistant S. aureus (MRSA). Here, we developed and characterized a swine model of topical microbiome perturbation and MRSA colonization. As in other model systems, topical antimicrobial treatment had little discernable effect on community diversity though overall microbial load was sensitive to any type of intervention, including swabbing. In parallel, we established a porcine skin culture collection and screened 7,700 isolates for MRSA inhibition. Inhibitory isolates were represented across all major phyla of the pig skin microbiota and did not have a strong preference for inhibiting closely related species, suggesting that relatedness is not a condition of antagonism. Using genomic and phenotypic criteria, we curated 3 isolates to investigate whether prophylactic colonization would inhibit MRSA colonization in vivo. The 3-member consortium together, but not individually, provided protection against MRSA colonization, suggesting cooperation and/or synergy among the strains. These findings reveal the porcine skin as an underexplored reservoir of skin commensal species with the potential to prevent MRSA colonization and infection.