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

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2021 · $346,488

## Abstract

Project Summary/Abstract
Natural products form a validated and preeminent source of new drug leads, but the low rate of new discoveries
and the limited access of bioactive compounds are challenging current natural products-based drug discovery
and development. The overall goal of the PI’s research program is to access and expand chemical diversity of
microbes by the use of innovative strategies, thereby advancing natural products research. The central
hypothesis of this work is that microbial genomes can be exploited to explore natural products and analogs.
Bioinformatics mining of biosynthetic gene clusters from thousands of microbial genomes have distinguished
microbes as the prominent source of an immense number of new therapeutically relevant compounds. However,
current discovery process is able to access only a small fraction of these compounds, underlining the urgent
need of new strategies. Enzymes as biocatalysts are proven alternatives for chemical synthesis in academic and
industrial settings. The biosynthesis of microbial natural products is enriched with functionally diverse enzymes.
Discovery of new enzymology from microbes can advance the synthesis of structural complex natural products
and analogs via chemical methods or biological approaches (e.g., synthetic biology). To achieve the goal and
test the hypothesis, research direction 1 of this proposal will focus on producing cyanobacterial natural products
using multiple synthetic biology chassis. Cyanobacteria are a prolific source of structurally and functionally
diverse natural products, but almost all cyanobacterial compounds are accessed only through the isolation from
collected field samples. The research direction 1 can lead to the robust, thorough exploration of cyanobacterial
strains directly from the genomes. Research direction 2 of this proposal will discover and characterize
synthetically significant enzymes from microbial BCs, aiding the access and expansion of chemical diversity of
natural products. The new enzymes discovered in direction 1 will also be characterized in direction 2 and can
then be used in direction 1 to produce natural and unnatural compounds, demonstrating the improved cost
efficiency. Specific attention in direction 2 will be to discover and characterize novel nitration enzymes. Together,
these two directions of the PI’s research program can afford innovative strategies that enable effective
exploitation of the seemingly limitless chemical diversity of microbes for discovery and development of new drugs
and allow the development of new chemical processes. These studies can also boost the transformation of
natural products research from small-scale pursuits to a genome-based high-throughput endeavor, therefore
potentially triggering a paradigm shift in natural products and drug research.

## Key facts

- **NIH application ID:** 10189650
- **Project number:** 5R35GM128742-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Yousong Ding
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,488
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189650

## Citation

> US National Institutes of Health, RePORTER application 10189650, Accessing and expanding microbial chemical diversity by synthetic biology and new enzymology (5R35GM128742-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189650. Licensed CC0.

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