Small Molecule in situ Resin Capture - an Organism Independent Strategy for Natural Product Discovery.

Microbial natural products remain a crucial source of lead compounds for drug discovery. Yet, commonly employed discovery techniques are plagued by the rediscovery of known compounds, a narrow taxonomic focus on the relatively few microbes that can be cultured, and laboratory growth conditions that do not support biosynthetic gene expression. Here we exploit a culture independent approach to microbial natural product discovery that we call the Small Molecule In situ Resin Capture (SMIRC) technique. SMIRC represents a new approach to mine natural products from underexplored "chemical space". We demonstrate the application of this approach with the discovery of numerous new compounds including cabrillospiral, which possesses a new carbon skeleton with a functional group not previously observed among natural products. In contrast to traditional culture-based methods, this compound first approach can capture structurally complex small molecules across all domains of life in a single deployment while relying on Nature to provide the complex and poorly understood environmental cues needed to elicit biosynthetic gene expression. We target marine habitats given the potential for chemical novelty, yet the SMIRC method is applicable across other environments. We demonstrate that SMIRC recovers novel compounds with sufficient yields for NMR-based structure assignment and employ a variety of approaches including expanded deployments, in situ cultivation, and metagenomics to address compound re-supply. This approach has the potential to provide unprecedented access to new natural product chemotypes with broad implications for drug discovery. ### Competing Interest Statement The authors have declared no competing interest.