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 <em>Streptomyces</em> bacteria encode the largest biosynthetic diversity by far, with <em>Amycolatopsis</em>, <em>Kutzneria</em> and <em>Micromonospora</em> also encoding substantial chemical diversity. Finally we find that several less-well-studied taxa such as Weeksellaceae (Bacteroidota), Myxococcaceae (Myxococcota), <em>Pleurocapsa</em> and Nostocaceae (Cyanobacteria) have potential to produce highly diverse secondary metabolites that warrant further investigation.