A family of lanthipeptides with anti-phage function

Abstract

AbstractBacteria synthesize natural products to adapt to their environment, where phage-bacteria interactions play a crucial role in bacterial ecology. Although a few natural products have been shown to protect bacteria from phage infection, the prevalence and diversity of chemical anti-phage defense remain largely unexplored. Here, we uncover a novel family of over 2000 lanthipeptide biosynthetic gene clusters from Actinobacteria that participate in anti-phage defense, which we named lanthiphages. Lanthiphages colocalize with other anti-phage systems in defense islands. We demonstrate that native lanthiphage expression protects the model strainStreptomyces coelicoloragainst diverse phages. Heterologous expression of four additional lanthiphage pathways shows that the anti-phage function is conserved across this family of biosynthetic gene clusters. Finally, we demonstrate that lanthiphage expression leads to the production of a novel compound and alters phage transcription. Our findings highlight that biosynthetic gene clusters with anti-phage functions can be successfully identified through genomic analysis. This work paves the way for the systematic mining of anti-phage natural products, which could constitute a novel reservoir of antiviral drugs.