Bacterial peptide deformylase inhibitors induce prophages in competitors

Abstract While antibiotics mediate chemical warfare among microbes, their roles in the wild extend beyond direct growth inhibition(1). Some antibiotics have the potential to mediate interference competition by triggering a bacterial stress response that subsequently activates endogenous viruses integrated in bacterial genomes (prophages). Canonically, this activation is regulated by the SOS response upon DNA damage. Here we show that a metabolite produced by natural isolates of Vibrio ordalii circumvents the SOS response by directly triggering prophage induction in other Vibrio species, co-occurring in the same environment. While the metabolite was previously classified as a broad-spectrum antibiotic, we observe how it acts as a peptide deformylase inhibitor that specifically induces certain prophages, even when target bacterial cells carry multiple other prophages. Its biosynthetic gene cluster, or ord cluster, also encodes its own peptide deformylase (OrdE) which provides self-immunity to producer strains. Likewise, among natural Vibrio isolates that carry similar prophages, resistance against the ord metabolite was found in those that had acquired a divergent second peptide deformylase. Finally, we show that prophage induction by the ord cluster prevents slower-growing producer strains from being outcompeted by their otherwise fast-growing competitors if they carry an inducible prophage. Thus, we demonstrate how natural products play additional impactful roles in communities beyond antibiotic activity and that prophage induction serves as an interference competition strategy, sustaining community diversity. Competing Interest Statement P.C.B. is a consultant to or holds equity in 10X Genomics, General Automation Lab Technologies/Isolation Bio, Next Gen Diagnostics, Cache DNA, Concerto Biosciences, Stately, Ramona Optics, Bifrost Biosystems, and Amber Bio. His laboratory has received research funding from Calico Life Sciences, Merck, and Genentech for unrelated work.