Genome Mining Analysis Uncovers the Previously Unknown Biosynthetic Capacity for Secondary Metabolites in Verrucomicrobia

Bacteria of the phylum Verrucomicrobia is widely distributed in diverse ecological environments. Their limited cultivability has greatly caused the significant knowledge gap surrounding their secondary metabolites and their mediating ecological functions. This study delved into the diversity and novelty of secondary metabolite biosynthetic gene clusters (BGCs) of Verrucomicrobia by employing a gene-first approach to investigate 2323 genomes. A total of 7552 BGCs, which encompassed 3744 terpene, 805 polyketide, 773 non-ribosomal peptide gene clusters, and 1933 BGCs of other biosynthetic origins, were identified. They were further classified into 3887 gene cluster families (GCFs) based on biosynthetic gene similarity clustering, of which only six GCFs contained reference biosynthetic gene clusters in the Minimum Information about a Biosynthetic Gene Cluster (MIBiG), indicating the striking novelty of secondary metabolites in Verrucomicrobia. Notably, 37.8% of these gene clusters were harbored by unclassified species of Verrucomicrobia phyla, members of which were highly abundant in soil environments. Furthermore, our comprehensive analysis also revealed Luteolibacter and Methylacidiphilum as the most prolific genera in terms of BGC abundance and diversity, with the discovery of a conservative and new NRPS-PKS BGC in Luteolibacter. This work not only unveiled the biosynthetic potential and genetic diversity of secondary metabolites of Verrucomicrobia but also provided a fresh insight for the exploration of new bioactive compounds.