The polytheonamides are among the most complex and biosynthetically distinctive natural products known to date. These potent peptide cytotoxins are derived from a ribosomal precursor processed by 49 mostly non-canonical posttranslational modifications. As the producer is a ‘microbial dark matter’ bacterium only distantly related to any cultivated organism, >70-step chemical syntheses have been developed to access these unique compounds. Here, we mined prokaryotic diversity to establish a synthetic platform based on the new host Microvirgula aerodenitrificans that produces hypermodified peptides within two days. Using this system, we generated the aeronamides, new polytheonamide-type compounds with near-picomolar cytotoxicity. Aeronamides, as well as the polygeonamides produced from deep-rock biosphere DNA, contain the highest numbers of d-amino acids in known biomolecules. With increasing bacterial genomes being sequenced, similar host mining strategies might become feasible to access further elusive natural products from uncultivated life.
Bibliographical noteFunding Information:
We thank R. Bernier-Latmani and R. Stepanauskas for discussions and DNA samples that contained the geo and vep cluster, and B. I. Morinaka and R. Ueoka for technical advice. This work was supported by the Swiss National Science Foundation (205320_185077), the Helmut Horten Foundation, the EU (ERC Advanced Grant ‘SynPlex’, BluePharmTrain) and Novartis (17B075) to J.P.
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.