A family of lanthipeptides with anti-phage function

Bacteria produce natural products to adapt to their environments, with phage interactions as major ecological and evolutionary drivers. While some natural products protect bacteria from phages, the prevalence and diversity of chemical anti-phage defenses remain largely unexplored. Here, we identify a widespread family of lanthipeptide biosynthetic gene clusters (BGCs) in Actinobacteria, which we term lanthivirin BGCs, that confer anti-phage activity. Lanthivirin BGCs often colocalize with other defense systems in genomic defense islands. We demonstrate anti-phage activity both in a native Streptomyces context and through heterologous expression of six distinct lanthivirin systems. Mutational analyses of the biosynthetic machinery and core peptide show that lanthivirin maturation is required for anti-phage activity. Genetic and biochemical analyses during infection support a phage-protein-dependent inhibition of phage DNA replication, with no host toxicity. Our findings highlight the untapped potential of BGCs as sources of anti-phage natural products, offering a new avenue for discovering antiviral compounds.