Biosynthetic potential of the global ocean microbiome

8 pages, 4 figures, supplementary information https://doi.org/10.1038/s41586-022-04862-3.-- This Article is contribution number 130 of Tara OceansNatural microbial communities are phylogenetically and metabolically diverse. In addition to underexplored organismal groups1, this diversity encompasses a rich discovery potential for ecologically and biotechnologically relevant enzymes and biochemical compounds2,3. However, studying this diversity to identify genomic pathways for the synthesis of such compounds4 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 biosynthetic gene 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 biosynthetic gene clusters, several of which were found in previously unsuspected phylogenetic groups. Among these groups, we identified a lineage rich in biosynthetic gene clusters (‘Candidatus Eudoremicrobiaceae’) that belongs to an uncultivated bacterial phylum and includes some of the 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 environmentsThis work was supported by funding from the ETH and the Helmut Horten Foundation; the Swiss National Science Foundation (SNSF) through project grants 205321_184955 to S.S., 205320_185077 to J.P. and the NCCR Microbiomes (51NF40_180575) to S.S.; by the Gordon and Betty Moore Foundation (https://doi.org/10.37807/GBMF9204) and the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 101000392 (MARBLES) to J.P.; by an ETH research grant ETH-21 18-2 to J.P.; and by the Peter and Traudl Engelhorn Foundation and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 897571 to C.C.F. S.L.R. was supported by an ETH Zurich postdoctoral fellowship 20-1 FEL-07. M.L., L.M.C. and G.Z. were supported by EMBL Core Funding and the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft, project no. 395357507, SFB 1371 to G.Z.). M.B.S. was supported by the NSF grant OCE#1829831. C.B. was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement Diatomic, no. 835067). S.G.A. was supported by the Spanish Ministry of Economy and Competitiveness (PID2020-116489RB-I00). M.K. and H.M. were funded by the SNSF grant 407540_167331 as part of the Swiss National Research Programme 75 ‘Big Data’. M.K., H.M. and A.K. are also partially funded by ETH core funding (to G. Rätsch)With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)Peer reviewe