Nocathioamides, Uncovered by a Tunable Metabologenomic Approach, Define a Novel Class of Chimeric Lanthipeptides

The increasing number of available genomes, in combination with advanced genome mining techniques, unveiled a plethora of biosynthetic gene clusters (BGCs) coding for ribosomally synthesized and post‐translationally modified peptides (RiPPs). The products of these BGCs often represent an enormous resource for new and bioactive compounds, but frequently, they cannot be readily isolated and remain cryptic. Here, we describe a tunable metabologenomic approach that recruits a synergism of bioinformatics in tandem with isotope‐ and NMR‐guided platform to identify the product of an orphan RiPP gene cluster in the genomes of Nocardia terpenica IFM 0406 and 0706T. The application of this tactic resulted in the discovery of nocathioamides family as a founder of a new class of chimeric lanthipeptides I. Chimeric Lanthipeptides: Employing a tunable metabologenomic approach, nocathioamides A–C were isolated and elucidated. They inaugurate a new RiPP family, characterized by a unique and hyper degree of modifications, including an intramolecular imide bridge.