Discovery and Characterization of a Myxobacterial Lanthipeptide with Unique Biosynthetic Features and Anti-inflammatory Activity

The genomes of myxobacteria harbor a variety of biosyntheticgeneclusters encoding numerous secondary metabolites, including ribosomallysynthesized and post-translationally modified peptides (RiPPs) withdiverse chemical structures and biological activities. However, thebiosynthetic potential of RiPPs from myxobacteria remains barely explored.Herein, we report a novel myxobacteria lanthipeptide myxococin identifiedfrom Myxococcus fulvus. Myxococinsrepresent the first example of lanthipeptides, of which the characteristicmultiple thioether rings are installed by employing a Class II lanthipeptidesynthetase MfuM and a Class I lanthipeptide cyclase MfuC in a cascadedway. Unprecedentedly, we biochemically characterized the first M61family aminopeptidase MfuP involved in RiPP biosynthesis, demonstratingthat MfuP showed the activity of an endopeptidase activity. MfuP isleader-independent but strictly selective for the multibridge structureof myxococin A and responsible for unwrapping two rings via amidebond hydrolysis, yielding myxococin B. Furthermore, the X-ray crystalstructure of MfuP and structural analysis, including active-site mutations,are reported. Finally, myxococins are evaluated to exhibit anti-inflammatoryactivity in lipopolysaccharide-induced macrophages without detectablecytotoxicity.