Establishing conserved biosynthetic gene clusters of the phylum Myxococcota

A surge in sequenced myxobacteria catalyzed by advancements in long-read genome and metagenome sequencing has provided sufficient data to scrutinize the conserved biosynthetic gene clusters (BGCs) within the phylum Myxococcota. Provided the utility of myxobacteria in environmental nutrient cycles and discovery of novel therapeutic leads, we sought to determine any conserved specialized metabolism in the phylum. Using a pan-genome approach to analyze 11 genera and 195 sequenced genomes, including 10 newly reported myxobacterial isolates, we observed five conserved BGCs. All five clusters encode for characterized metabolites with established ecological roles for four of the metabolites, and none of the metabolites are known toxins. Validation of our approach was done by analyzing Myxococcota genera without sufficient sequenced representatives for pan-genome analysis to observe the presence/absence of these five clusters. This approach enabled observation of genus-level conservation of BGCs with varying degrees of confidence due to the diversity of sequenced species within each genus. The indigoidine BGC typically found in Streptomyces spp. was notably conserved in Melittangium; heterologous expression of the core biosynthetic gene bspA in Escherichia coli and subsequent detection of indigoidine confirmed the identity of the indigoidine cluster. Conserved BGCs in myxobacteria reveal maintenance of biosynthetic pathways and cognate metabolites with ecological roles as chemical signals and stress response; these observations suggest competitive specialization of secondary metabolism and toxin production in myxobacteria.

Critical contributions to soil nutrient cycles by predatory bacteria, including the Myxococcota, and utility as a resource for the discovery of novel enzymology and metabolism motive continued isolation and characterization of myxobacteria from the environment. Each of these motivating factors involves specialized metabolites produced by myxobacteria and the biosynthetic gene clusters (BGCs) responsible for their assembly. Primarily associated with the predatory lifestyles of myxobacteria, myxobacterial specialized metabolites have been pursued as therapeutic leads for novel antibacterials, antifungals, anthelmintics, and cancer therapies. Despite these efforts and the observation that nearly all genera within the Myxococcota have an extraordinary number of BGCs, there is no consensus view of the conserved BGCs in the phylum. Our study revealed the core BGCs consistently present throughout the phylum. By reporting these core specialized metabolites and their ecological roles, we hope to streamline the discovery and investigation of specialized metabolism in myxobacteria.