# Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $381,375

## Abstract

Project summary: The development of therapies inspired by the human microbiome is at least in part limited
by our lack of understanding of how human associated (HA-) bacteria communicate with their human host.
Human microbiome sequencing studies show strong correlations between changes in bacterial populations
and human health. Despite these correlations and the evidence linking HA-bacteria to disease in mice, the
mechanistic details of how HA-bacteria specifically affect mammalian physiology remain largely unknown. In
other environments, bacteria are known to rely heavily on low molecular weight compounds (small molecules
or natural products) to interact with other organisms. Similarly, we expect that HA-bacteria are likely to use
small molecules to interact with their human hosts. Mounting evidence suggests that, although each human
microbiome is composed of a complex collection of bacteria, a much smaller number of species is highly
prevalent across the majority of individuals. While we don't know exactly which HA-bacteria are responsible for
maintaining human health or causing disease, we hypothesize that small molecules produced by these
commonly encountered HA-bacteria are likely to play an important role in regulating human physiology. The
central aim of this proposal is to screen metabolites produced by the most commonly observed human HA-
bacteria in high-throughput GPCR activity assays to identify GPCR-active small molecules and the biosynthetic
gene clusters that produce them. GPCRs constitute the largest family of eukaryotic trans-membrane receptors.
They are known to play diverse and profound roles in human biology and are prone to regulation by small
molecules. Based on the fact that GPCRs play such an extensive role in transforming chemical information
from the environment into biological signals in eukaryotic cells, I believe that HA-bacteria likely affect host
physiology through the production of small molecules that interact with GPCRs. The two Aims of this proposal
will result in (1) the identification, isolation, and structure elucidation of HA-bacteria-encoded metabolites that
interact with diverse GPCRs and (2) the characterization of the biosynthetic gene clusters for these novel
metabolites. These studies will help to illuminate the mechanistic details of how HA-bacteria shape human
health and lay the groundwork for developing HA-bacteria that produce GPCR-active ligands into therapies for
controlling human physiology. The human microbiome is reported to influence complex pathophysiological
processes ranging from the regulation of the immune system to the development of the brain and the central
nervous system. Changes in human HA-bacterial populations are associated with diseases that affect over 200
million Americans including obesity, diabetes, inflammatory bowel disease, autism, irritable bowel syndrome,
and cirrhosis among many others. Therapies derived from human HA-bacteria have potential utility in
controlling dive...

## Key facts

- **NIH application ID:** 9959340
- **Project number:** 5R01AT009562-04
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** SEAN F BRADY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,375
- **Award type:** 5
- **Project period:** 2017-07-14 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959340

## Citation

> US National Institutes of Health, RePORTER application 9959340, Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria (5R01AT009562-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9959340. Licensed CC0.

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