A global survey of specialized metabolic diversity encoded in bacterial genomes

Bacterial secondary metabolites have been studied for decades for their usefulness as drugs, such as antibiotics. However, the identification of new structures has been decelerating, in part due to rediscovery of known compounds. Meanwhile, multi-resistant pathogens continue to emerge, urging the need for new antibiotics. It is unclear how much chemical diversity exists in Nature and whether discovery efforts should be focused on established antibiotic producers or rather on understudied taxa. Here, we surveyed around 170,000 bacterial genomes as well as several thousands of Metagenome Assembled Genomes (MAGs) for their diversity in Biosynthetic Gene Clusters (BGCs) known to encode the biosynthetic machinery for producing secondary metabolites. We used two distinct algorithms to provide a global overview of the biosynthetic diversity present in the sequenced part of the bacterial kingdom. Our results indicate that only 3% of genomic potential for natural products has been experimentally discovered. We connect the emergence of most biosynthetic diversity in evolutionary history close to the taxonomic rank of genus. Despite enormous differences in potential among taxa, we identify Streptomyces as by far the most biosynthetically diverse based on currently available data. Simultaneously, our analysis highlights multiple promising high-producing taxa that have thus far escaped investigation.