# Discovery and Biosynthesis of Bacterial Terpenoids

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2021 · $226,713

## Abstract

PROJECT SUMMARY/ABSTRACT
 The long-term objectives of our research program are to (i) discover novel bacterial natural products
(NPs), (ii) elucidate the biosynthetic pathways and regulatory mechanisms of these NPs, and (iii) characterize
and utilize the discovered NPs and their biosynthetic enzymes for biomedical and biotechnological applications.
NPs are highly functionalized and evolutionarily optimized small molecules that possess unrivaled chemical
and structural diversities, resulting in a wide range of biological activities. Terpenoids, the largest and most
structurally diverse family of NPs, are considered rare in bacteria; only ~1.2% of known terpenoids are of
bacterial origin. However, genomics studies revealed that the biosynthetic enzymes responsible for terpenoid
biosynthesis are widely distributed in bacteria, particularly actinobacteria. We hypothesize that (i) bacterial
terpenoids are considerably underestimated among current NP libraries and the discovery and characterization
of novel terpenoids will lead to new drug leads and (ii) understanding the sequence-structure-function
relationships of terpenoid biosynthetic enzymes will lead to new opportunities in genome mining, combinatorial
biosynthesis, and oxidative biocatalysis. Our initial efforts follow two research directions that address
immediate needs and will set the stage for continued success in the field of terpenoid discovery and
biosynthesis. In the first direction, we will use an integrated genomics–metabolomics approach to discovery
novel bacterial terpenoids from bacteria. This will include the development of new and innovative
methodologies for targeted identification of complex bacterial terpenoids and the activation or upregulation of
terpenoid biosynthetic gene clusters. In the second direction, we will elucidate the biosynthetic pathways of
both new and known bacterial terpenoids and functionally, mechanistically, and structurally characterize
terpene synthases and their associated oxidative enzymes, particularly cytochrome P450s. We will use a
rigorous multidisciplinary approach involving genome mining, bioinformatics analysis, in vivo pathway
engineering, (un)natural product isolation and structural determination, in vitro enzymology, and protein X-ray
crystallography. Our experience in terpenoid biosynthesis and enzymology and our significant progress in
both research directions supports the feasibility of the proposed research and that we are well-suited to
establish and sustain a successful independent program in this field. In addition, we have established several
key collaborations with leaders in the fields of synthetic biology, NP drug discovery, and X-ray
crystallography that further strengthen this research program. Expected outcomes of this research program
include the revelation of the bacterial terpenome, understanding the underlying principles of how terpene
synthases dictate terpene cyclization, and the exploitation of naturally evolved oxidative...

## Key facts

- **NIH application ID:** 10273479
- **Project number:** 1R35GM142574-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Jeffrey Daniel Rudolf
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $226,713
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273479

## Citation

> US National Institutes of Health, RePORTER application 10273479, Discovery and Biosynthesis of Bacterial Terpenoids (1R35GM142574-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10273479. Licensed CC0.

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