A widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress

Abstract

Ribosomally synthesized, post-translationally modified peptides (RiPPs) are increasingly known to play prominent roles in bacterial adaptation. Herein, we identified and characterized a family of RiPP metallophores with rare 5-thiooxazole motifs, whose production is induced by transition metal stress in a number of pathogenic and environmental bacteria. Using Caulobacter vibrioides as a model, we demonstrated that the so-called bufferins confer protection to the bacteria from copper by complexing with the metal. Bufferin biosynthesis requires a multinuclear non-heme iron-dependent oxidase (MNIO, DUF692 family) and its partner protein to install thiooxazoles on Cys residues. By contrast, a hallmark feature of bufferin precursors, the N-terminal signal peptide sequence, is not essential for this transformation. Bufferin-like gene clusters are widespread in Eubacteria, including several pathogens, and the C. vibrioides epitomize the largest two families of RiPPs involving MNIO enzymes. Our study unveils a widespread but overlooked bacterial strategy mediated by a new type of RiPPs to cope with copper stress encountered in the environment and in the phagosomes of predatory protists or mammalian hosts.