# Discovery of Antibiotics from Soil Microbiomes Using Metagenomics

> **NIH NIH R35** · ROCKEFELLER UNIVERSITY · 2024 · $678,000

## Abstract

Project Summary:
 Bacterial natural products have a long history of serving as lead structures for the development of new
therapeutically relevant small molecules. Despite the tremendous early success of bacterial natural product
discovery programs, both academic and industrial drug screening efforts have largely deprioritized natural
products in recent years due to unacceptably high rediscovery rates, which were often taken as an indication
that nature had few novel small molecules left for us to identify. Extensive sequencing of both bacterial
genomic and metagenomic DNA indicates that this is, in fact, not the case. Instead, it appears that we have
just begun to scratch the surface of the structural and functional diversity of small molecules encoded by the
global microbiome. In most environments uncultured bacteria still significantly outnumber their cultured
counterparts, and even when it is possible to grow bacteria in the laboratory they usually only express a small
subset of their natural product biosynthetic gene clusters. My research group is focused on the development of
culture-independent (metagenomic) approaches for identifying novel natural products encoded provides a
means of accessing this large fraction of previously inaccessible biosynthetic diversity. In these studies, the
need to culture bacteria is circumvented by extracting DNA directly from environmental samples and cloning it
into easily cultured bacteria. This proposal is designed to continue our development of culture-independent
methods for accessing the natural products encoded in soil metagenomes and to increasingly apply these
methods to the discovery and characterization of new bioactive small molecules. In particular, our studies will
include the development of new sequence-based and functional metagenomic screening methods as well as
the use of heterologous expression and synthetic bioinformatic natural product discovery approaches to
generate novel small molecules from soil metagenome derived biosynthetic gene clusters. Method develop
studies will be focus on overcoming key technical hurdles to enable the more efficient and higher throughput
discovery of structurally and mechanistically different natural products from metagenomes using both
bioinformatic and unbiased functional screening approaches. As with traditional natural product discovery
programs, our ultimate goal is to identify bioactive small molecules that have the potential to be used as lead
structures for the development of novel therapeutics. Although our metagenomic methods can be applied to
the identification of compounds that can target almost any disease, we will primarily focus on the discovery of
new antibiotics. This choice is driven by the long history of natural products being the most productive source
of potent antibiotics with unique modes of actions and the clear biomedical need for new antibiotics that are
effective against clinically relevant, multi-drug resistant, Gram-positive and...

## Key facts

- **NIH application ID:** 10915395
- **Project number:** 5R35GM122559-07
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** SEAN F BRADY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,000
- **Award type:** 5
- **Project period:** 2017-05-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915395

## Citation

> US National Institutes of Health, RePORTER application 10915395, Discovery of Antibiotics from Soil Microbiomes Using Metagenomics (5R35GM122559-07). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10915395. Licensed CC0.

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