Small Moleculein situResin Capture – A Compound First Approach to Natural Product Discovery

Abstract

AbstractMicrobial natural products remain an important resource for drug discovery. Yet, commonly employed discovery techniques are plagued by the rediscovery of known compounds, the relatively few microbes that can be cultured, and laboratory growth conditions that do not elicit biosynthetic gene expression among myriad other challenges. Here we introduce a culture independent approach to natural product discovery that we call the Small Molecule In situ Resin Capture (SMIRC) technique. SMIRC exploits in situ environmental conditions to elicit compound production and represents a new approach to access poorly explored chemical space by capturing natural products directly from the environments in which they are produced. In contrast to traditional 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 illustrate the effectiveness of SMIRC in marine habitats with the discovery of numerous new compounds and demonstrate that sufficient compound yields can be obtained for NMR-based structure assignment. Two new compound classes are reported including one novel carbon skeleton that possesses a functional group not previously observed among natural products and a second that possesses potent biological activity. We introduce expanded deployments, in situ cultivation, and metagenomics as methods to facilitate compound discovery, enhance yields, and link compounds to producing organisms. This compound first approach can provide unprecedented access to new natural product chemotypes with broad implications for drug discovery.Significance StatementPharmaceutically relevant microbial natural products have traditionally been discovered using a ‘microbe-first’ approach in which bioassays are used to guide the isolation of active compounds from crude culture extracts. While once productive, it is now widely recognized that this approach fails to access the vast chemical space predicted from microbial genomes. Here, we report a new approach to natural product discovery in which compounds are captured directly from the environments in which they are produced. We demonstrate the applications of this technique with the isolation and identification of both known and new compounds including several that possess new carbon skeletons and one with promising biological activity.