Compendium of specialized metabolite biosynthetic diversity encoded in bacterial genomes

Bacterial specialized metabolites are a proven source of antibiotics and cancer therapeutics, but whether we have sampled all the secondary metabolite chemical diversity  of cultivated bacteria is not known. We analysed ~ 170,000 bacterial genomes and ~ 47,000 metagenome assembled genomes (MAGs) using a modified BiG-SLiCE and the new clust-o-matic algorithm. We found that only 3% of the natural products potentially encoded in bacterial genomes have been experimentally characterized. We show that the variation of secondary metabolite biosynthetic diversity drops significantly on a genus level, identifying it as an appropriate taxonomic rank for comparison. Equal comparison of genera based on Relative Evolutionary Distance revealed that Streptomyces bacteria encode the largest biosynthetic diversity by far, with Amycolatopsis, Kutzneria and Micromonospora also encoding substantial chemical diversity. Finally we find that several less-well-studied taxa such as Weeksellaceae (Bacteroidota), Myxococcaceae (Myxococcota), Pleurocapsa and Nostocaceae (Cyanobacteria) have potential to produce highly diverse secondary metabolites that warrant further investigation.