Microsclerodermins from terrestrial myxobacteria: an intriguing biosynthesis likely connected to a sponge symbiont

The microsclerodermins are unusual peptide natural products exhibiting potent antifungal activity reported from marine sponges of the genera Microscleroderma and Theonella . We here describe a variety of microbial producers of microsclerodermins and pedeins among myxobacteria along with the isolation of several new derivatives. A retrobiosynthetic approach led to the identification of microsclerodermin biosynthetic gene clusters in genomes of Sorangium and Jahnella species, allowing for the first time insights into the intriguing hybrid PKS/NRPS machinery required for microsclerodermin formation. This study reveals the biosynthesis of a "marine natural product" in a terrestrial myxobacterium where even the identical structure is available from both sources. Thus, the newly identified terrestrial producers provide access to additional chemical diversity; moreover, they are clearly more amenable to production optimization and genetic modification than the original source from the marine habitat. As sponge metagenome data strongly suggest the presence of associated myxobacteria, our findings underpin the recent notion that many previously described "sponge metabolites" might in fact originate from such microbial symbionts.