# Accessing and expanding microbial bioactive chemical diversity by synthetic biology and new enzymology

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2023 · $386,145

## Abstract

Project Summary/Abstract
Natural products (NPs) form a validated and preeminent source of new drug leads, but the low rate of new
discoveries and the limited access to bioactive compounds are challenging current NPs-based drug discovery
and development. Over the past decades, genome mining has become an important way for NP discovery. This
transformative research strategy combines functional genomics and bioinformatics to associate biosynthetic
gene clusters (BGCs) with potential chemical entities. The success of this strategy is supported by increasing
and rapid access to (meta)genomic data, from which diverse rule-based and -free bioinformatics tools enable
depicting the BGCs of different compound families and even assessing their novelty and potential bioactivity.
However, a fundamental challenge faced by genome mining research is how to produce sufficient amounts of
novel, bioactive NPs from mined BGCs. The overall goal of the PI's research program is to access and expand
the therapeutically relevant chemical diversity of microbes directly from their genomes. The central hypothesis
of this work is that microbial genomes can be exploited to produce bioactive NPs and analogs through synthetic
biology (SynBio) and enzymology research. SynBio has achieved many notable successes in the production of
bioactive compounds over the past two decades. In the NP discovery, SynBio studies can allow the expression
of natural and designed BGCs in capable chasses. In parallel, the biosynthesis of microbial NPs is enriched with
functionally diverse enzymes that lend enabling strategies to produce key intermediates and analogs of bioactive
NPs. To achieve the goal and test the hypothesis, this renewal will pursue two interlinked research directions.
Direction 1 will focus on the discovery and production of bioactive NPs from less-explored resources, particularly
in marine entrainment. To maximize the success, our SynBio research will develop and use chasses of multiple
bacterial phyla. Research direction 2 of this proposal will discover and characterize synthetically significant
enzymes using a diverse set of approaches, aiding the access and expansion of therapeutically relevant
chemical diversity of NPs. New enzymes found in Direction 1 will be characterized in Direction 2 and can then
support the mining of new BGCs in Direction 1, leading to tight integration and mutual support of the two
directions. Together, these two directions can afford innovative strategies that enable the effective exploitation
of bioactive NPs from the genomes of less-studied microbes. These studies can also boost the transformation
of NP research from small-scale pursuits to a genome-based high-throughput endeavor, therefore supporting
the paradigm shift in NP-based drug research.

## Key facts

- **NIH application ID:** 10621001
- **Project number:** 2R35GM128742-06
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Yousong Ding
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $386,145
- **Award type:** 2
- **Project period:** 2018-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10621001

## Citation

> US National Institutes of Health, RePORTER application 10621001, Accessing and expanding microbial bioactive chemical diversity by synthetic biology and new enzymology (2R35GM128742-06). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10621001. Licensed CC0.

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