As a monophyletic group, the myxobacteria are known to produce a broad spectrum of secondary metabolites. However, the degree of metabolic diversity that can be found within a single species remains unexplored. The model species Myxococcus xanthus produces several metabolites also present in other myxobacterial species, but only one compound unique to M. xanthus has been found to date. Here, we compare the metabolite profiles of 98 M. xanthus strains that originate from 78 locations worldwide and include 20 centimeter-scale isolates from one location. This screen reveals a strikingly high level of intraspecific diversity in the M. xanthus secondary metabolome. The identification of 37 nonubiquitous candidate compounds greatly exceeds the small number of secondary metabolites previously known to derive from this species. These results suggest that M. xanthus may be a promising source of future natural products and that thorough intraspecific screens of other species could reveal many new compounds of interest.Prokaryotes continue to provide important leads in the search for medically important bioactive natural products (1, 11). In particular, the myxobacteria have emerged as a promising source of natural products that exhibit highly diverse structures and biological activities (9). While most myxobacterial genera produce secondary metabolites, difficulties with cultivation and genetic manipulation hinder exploitation of the biosynthetic potential of many species. In contrast, the relatively fast growth and extensive genetic characterization of Myxococcus xanthus make the identification of natural products in this model species of particular interest.Myxococcus xanthus has been thoroughly investigated due to its amazing social behaviors, which include coordinated swarming over surfaces and a complex life cycle that culminates in the formation of multicellular fruiting bodies under starvation conditions (23). However, little attention has been paid to secondary metabolite production in this model species. M. xanthus strain DK1622 is the genotype most commonly studied with respect to social interactions and development. This strain has been found to produce several secondary metabolites, including the myxochromids (27), myxalamids (13), the antibiotic myxovirescin (8), and the siderophore myxochelin (15) (Fig. 1A). The molecular basis of synthesis for these compounds has been studied in some detail (25,26,30) and has been greatly facilitated by the availability of the DK1622 genome sequence (10). Very recently, a novel secondary metabolite class unique to M. xanthus, the DKxanthenes, was characterized and was shown to be essential for viable-spore formation (18). Additional reports of secondary metabolites from M. xanthus are limited to cittilin (20) and the antibiotics saframycin (12) and althiomycin (16).Most of these M. xanthus compounds are polyketides or nonribosomal peptides or hybrids thereof, and their biosynthesis is accomplished by large multienzyme complexes, the polyketide synthases (PKSs) or the nonri...

No abstract

Cittilins are secondary metabolites from myxobacteria comprised of three L-tyrosines and one L-isoleucine forming a bicyclic tetrapeptide scaffold with biaryl and aryl-oxygen-aryl ether bonds. Here we reveal that cittilins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products, for which only the crocagins have been reported from myxobacteria. A 27 amino acid precursor peptide harbors a C-terminal four amino acid core peptide, which is enzymatically modified and finally exported to yield cittilins. The small biosynthetic gene cluster responsible for cittilin biosynthesis also encodes a cytochrome P450 enzyme and a methyltransferase, whereas a gene encoding a prolyl endopeptidase for the cleavage of the precursor peptide is located outside of the cittilin biosynthetic gene cluster. We