Intra-species competition combats vancomycin-resistant enterococci.

Vancomycin-resistant Enterococcus (VRE) is a leading cause of multidrug-resistant infections in hospitalized patients, yet no reproducible microbiota therapies exist to selectively displace it. Here we harness intra-species competition within Enterococcus to suppress VRE colonization. Through in vitro screening and mouse colonization models, we identified a single antibiotic-susceptible strain, E. faecalis X98, that significantly reduced VRE burden both in vitro and in mouse experiments, whereas multi-strain consortia failed due to competitive interference among consortium members. In parallel, we subjected the vancomycin-sensitive strain E. faecalis OG1RF to phage selection, which produced a prophage-integrated derivative with convergent glycosyltransferase mutations that secreted a VRE-killing factor, conferring enhanced antagonism even without exogenous phage. These findings reveal ecological and evolutionary principles for selecting strains as targeted microbial therapeutics. Exploiting intra-species antagonism and phage-driven evolution provides a practical framework for developing microbiota-based interventions that minimize collateral damage to the microbiome while addressing antibiotic-resistant pathogens.