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

Abstract

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.

Progress and challenges in exploring aquatic microbial communities using non-targeted metabolomics

“…Multi-dimensional DOM fractionation and LC-MS/MS analysis, combined with bioactivity screening approaches, such as cytological profiling high content screening methods or antimicrobial assays, could link DOM chemical composition to biological functions. When done at high resolution and scale, identifying new natural products and their biological properties can be done directly from environmental samples [153]. Such developments will not only drastically improve our understanding of the DOM black box, but also unleash its tremendous molecular complexity as a potential source of structural and pharmaceutical/biotechnological novelty.…”

In Situ Capture and Real-Time Enrichment of Marine Chemical Diversity

“…I‑SMEL does not need to stay flat or be maintained on a flat surface to work. Collectively, these technical characteristics make I‑SMEL stand out compared to previously developed in situ devices. ,, …”

“…Collectively, these technical characteristics make I-SMEL stand out compared to previously developed in situ devices. 23 , 26 , 28 …”

“…However, the global concern for biological resources management and biodiversity conservation has significantly slowed down natural product chemistry in the past, whereas attempts to cultivate marine organisms have not provided sustainable biosourcing yet. Therefore, the idea of alternative SPE approaches to sustainably access marine specialized EMs under natural conditions emerged − with the objective of trapping the molecules of interest without harvesting the producing organisms.…”

The insect microbiome is a vast source of bioactive small molecules

“…390 To cover uncultured microorganisms with great biosynthetic gene cluster potential conditioned by these environments, in situ techniques can be adapted to directly extract compounds from the colony environments in which they are produced. 391 Furthermore, the prospect of using insect microbiomes as a source of natural products for targeted approaches against parasitic diseases is particularly promising. Insect vectors of parasitic diseases represent a direct interface between microorganisms and human pathogens.…”