Widespread hypermodified β-helical peptides in common bacteria

ABSTRACT

Polytheonamides are extraordinarily complex and potent ribosomal peptide cytotoxins featuring up to 50 mostly non-canonical post-translational modifications, including 18 d-amino acids. They act by forming minimalistic, unimolecular transmembrane ion channels that adopt a β-helical structure. Only a few related natural products are known, and they occur mostly in uncultivated, poorly studied bacteria. Here, we report the genomic discovery of a large, cryptic peptide family, termed origamins, that occurs in phylogenetically diverse, well-known bacteria, including Escherichia coli. Characterization of several pathways revealed striking similarities to polytheonamides, indicating convergent evolution of the complex maturation pattern. These include up to 44 modifications, a β-helical structure, and cytotoxic activity. A high prevalence in human-associated bacteria, including symbionts and pathogens, suggests widespread roles in host-microbiome interactions