Small molecule in situ resin capture provides a compound first approach to natural product discovery

Alexander Bogdanov, Mariam N. Salib, Alexander B. Chase, Heinz Hammerlindl, Mitchell N. Muskat, Stephanie Luedtke, Elany Barbosa Silva, Anthony J. O’Donoghue, Lani F. Wu, Steven J. Altschuler, Tadeusz F. Molinski () and Paul R. Jensen ()
Additional contact information
Alexander Bogdanov: San Diego
Mariam N. Salib: San Diego
Alexander B. Chase: San Diego
Heinz Hammerlindl: San Francisco
Mitchell N. Muskat: San Diego
Stephanie Luedtke: San Diego
Elany Barbosa Silva: San Diego
Anthony J. O’Donoghue: San Diego
Lani F. Wu: San Francisco
Steven J. Altschuler: San Francisco
Tadeusz F. Molinski: San Diego
Paul R. Jensen: San Diego

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth’s microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method to obtain natural products directly from the environments in which they are produced. We use SMIRC to capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features that are, to the best of our knowledge, unprecedented among natural products. Applications across diverse marine habitats reveal biome-specific metabolomic signatures and levels of chemical diversity in concordance with sequence-based predictions. Expanded deployments, in situ cultivation, and metagenomics facilitate compound discovery, enhance yields, and link compounds to candidate producing organisms, although microbial community complexity creates challenges for the later. This compound-first approach to natural product discovery provides access to poorly explored chemical space and has implications for drug discovery and the detection of chemically mediated biotic interactions.

Date: 2024
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DOI: 10.1038/s41467-024-49367-x

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