Ó³»­´«Ã½

Enterococci are major causes of multidrug-resistant hospital infections, underscoring the need for new antibacterial strategies. Here, we describe a previously unrecognized inhibitor class, efagins ( phe-related hibitor). Efagins are intrinsic to , the most widely distributed generalist among enterococci, and are structurally reminiscent of phage tails yet show only distant evolutionary relatedness to known phages or phage-like elements. The 14.6-kb efagin gene cluster is highly conserved except for a tail fiber-like encoding region that varies across five distinct classes. These classes correlate with differences in the rhamnose-rich Epa cell wall polysaccharide, the efagin binding target as demonstrated by domain-swap experiments. We identified at least 20 genotypes, and the efagins characterized here inhibit strains representing 17 of them. Importantly, efagin activity extends beyond : they inhibit multiple enterococcal species, including lineages of vancomycin-resistant , highlighting their potential as precision antibacterials.