Marine Metagenome Mining Reveals Lanthipeptides Colwesin A–C, Exhibiting Novel Ring Topology and Anti-inflammatory Activity

Marine natural products are promising sources for drug discovery due to their unique structures and diverse biological activities. The establishment of the Global Marine Microbiome Genome Catalogue (GOMC) has significantly expanded the repository of natural products derived from marine-associated bacteria. In this study, we identified the Class I lanthipeptide biosynthetic gene cluster <i>col</i> from <i>Colwellia_A</i> sp. based on the GOMC database. Through heterologous expression in <i>Escherichia coli</i> and subsequent structural analysis, we characterized three novel lanthipeptides, colwesins A-C, which possess unique cyclic structures characterized by an exceptionally large number of thioether rings. To the best of our knowledge, colwesin C is the first lanthipeptide simultaneously containing locked, nonoverlapped, and nested ring topologies. These findings highlight the robust ring-forming capacity of Class I lanthipeptide synthetases. Colwesins A-C were found to exhibit anti-inflammatory activity in lipopolysaccharide-induced mouse macrophage RAW264.7 cell lines without detectable cytotoxicity. Overall, our results broaden our understanding of the structural diversity of marine-derived lanthipeptides.