Antibiotic-resistance plasmids encode Evangelion, a widespread mobile antiphage defence system

Abstract Plasmids are major drivers of antibiotic resistance, but whether they also shape bacterial susceptibility to phages remains unexplored. Here, we identify Evangelion, a single-gene anti-phage defence system encoded by a naturally occurring plasmid in methicillin-resistant Staphylococcus aureus (MRSA), where it protects against lytic Silviavirus phages. Evangelion is frequently associated with antimicrobial-resistance plasmids, many of which carry multiple resistance genes and signatures of horizontal transfer, linking plasmid-associated resistance with bacterial immunity. Evangelion proteins combine a conserved DUF4062/TIR-like core with diversified auxiliary regions, revealing an evolutionarily conserved defence architecture adapted to distinct phage environments. Genetic, structural and evolutionary analyses support a model in which Eva01 responds to intracellular phage replication-associated processes and couples activation of its DUF4062 effector to NAD⁺ depletion and abortive infection. Distinct Evangelion lineages protect against different phage groups, suggesting that diversification of their auxiliary regions contributes to adaptation to distinct host-phage environments. Together, our findings define Evangelion as a family of mobile anti-phage systems and reveal that antimicrobial-resistance plasmids can couple antibiotic resistance with anti-phage immunity, potentially shaping bacterial susceptibility to both antibiotics and therapeutic phages.