Recent advances in discovery and biosynthesis of ribosomally synthesized and post-translationally modified peptides...

Covering: This review summarizes recent advances in the discovery, biosynthesis, and bioactivity of RiPP-derived lipopeptides, covering studies published up to 2024.Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse superfamily of natural products unified by a common biosynthetic logic: The peptide backbone is genetically encoded, and the translated precursor peptide undergoes a series of post-translational modifications catalyzed by maturase enzymes to produce the final bioactive compound. Despite their structural complexity, RiPPs are encoded by relatively small biosynthesis gene clusters. RiPP maturase enzymes are diverse and often promiscuous, offering significant biotechnological potential. However, their lack of conserved features makes genome-based discovery of novel RiPPs challenging. Recent advances in biosynthetic understanding and genome mining techniques have led to the identification of numerous uncharacterized RiPP biosynthetic gene clusters, often flanked by genes encoding non-RiPP moieties, in microbial genomes. Leveraging this information, a new class of natural products, hybrids of RiPPs and non-RiPP elements, has recently been discovered. Among them, RiPPs bearing fatty acyl groups, referred to as RiPP-derived lipopeptides, represent a newly emerging class of lipopeptide natural products with significant antimicrobial activity.