Biosynthetic potential of the global ocean microbiome

Natural microbial communities are phylogenetically and metabolically diverse. In addition to underexplored organismal groups(1), this diversity encompasses a rich discovery potential for ecologically and biotechnologically relevant enzymes and biochemical compounds(2,3). However, studying this diversity to identify genomic pathways for the synthesis of such compounds(4) and assigning them to their respective hosts remains challenging. The biosynthetic potential of microorganisms in the open ocean remains largely uncharted owing to limitations in the analysis of genome-resolved data at the global scale. Here we investigated the diversity and novelty of biosyntheticgene clusters in the ocean by integrating around 10,000 microbial genomes from cultivated and single cells with more than 25,000 newly reconstructed draft genomes from more than 1,000 seawater samples. These efforts revealed approximately 40,000 putative mostly new biosyntheticgene clusters, several of which were found in previously unsuspected phylogenetic groups. Among these groups, we identified a lineage rich in biosyntheticgene clusters ('Candidatus Eudoremicrobiaceae') that belongsto an uncultivated bacterial phylum and includes some ofthe most biosynthetically diverse microorganisms in this environment. From these, we characterized the phospeptin and pythonamide pathways, revealing cases of unusual bioactive compound structure and enzymology, respectively. Together, this research demonstrates how microbiomics-driven strategies can enable the investigation of previously undescribed enzymes and natural products in underexplored microbial groups and environments.

Automated summary

Natural microbial communities are diverse and offer great potential for the discovery of enzymes and biochemical compounds. However, studying this diversity and assigning the synthesis of compounds to their hosts is challenging. In this study, we integrated microbial genomes from various sources and discovered thousands of new biosynthetic gene clusters, including in previously unsuspected phylogenetic groups. We identified a lineage rich in biosynthetic gene clusters and characterized the structures and enzymology of bioactive compounds. This research demonstrates the value of microbiomics-driven strategies in exploring previously undescribed enzymes and natural products.