# Identification and Biosynthesis of Dehydrated Nonribosomal Peptides from Streptomyces

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $74,284

## Abstract

PROJECT SUMMARY
Nonribosomal peptides are an important class of natural products which display great structural and functional
diversity. As many nonribosomal peptides act as antimicrobials, the identification of novel bioactive NRPs can
lead to the development of new therapeutics for the treatment of antimicrobial resistant microorganisms.
Dehydrated nonribosomal peptides, peptides derived from or containing one or more α,β-dehydroamino acids
(dhAAs), are key targets for further therapeutic development due to their structural rigidity, resistance to
proteolytic degradation, and enhanced chemical reactivity. The Li Lab has focused on a specific class of
dehydrated nonribosomal peptides whose biosynthesis stems from biosynthetic gene clusters (BGCs) containing
nonribosomal-peptide synthetases (NRPSs) with C domains which modify amino acids (CmodAA). We have
recently characterized a class of these CmodAA domains which dehydrates β-hydroxy amino acids to dhAAs in
nonribosomal peptide biosynthesis, and work from our lab and others has demonstrated that these CmodAAderived
nonribosomal peptides display a diverse array of bioactivities. However, the identity of many CmodAA derived
nonribosomal peptides is undiscovered, and their biosynthetic pathways and biological roles remain
uncharacterized. Through genome mining we have identified nearly 4,500 nonidentical CmodAA domains, many of
which are distributed among soil bacteria including Streptomyces. The research described herein is aimed to
elucidate the unknown products of several of these BGCs from Streptomyces and characterize the role of the
CmodAA domain in their biosynthesis. I will use a combination of in silico analysis of the biosynthetic gene clusters,
comparative metabolomics, genetic manipulation, and NMR analysis to elucidate the cryptic products of these
BGCs. Once the nonribosomal peptide structure has been determined, I will perform a battery of in vitro enzyme
assays to elucidate the core enzymes involved in nonribosomal peptide biosynthesis, and the biosynthetic role
of the CmodAA domains within each BGC. Completion of the proposed research will lead to the discovery of novel
CmodAA derived dhAA nonribosomal peptides with potential therapeutic applications. Furthermore, the findings of
this research will provide a base of knowledge that will extend to the discovery of other CmodAA containing BGCs
and characterization of their dhAA containing products.

## Key facts

- **NIH application ID:** 10901283
- **Project number:** 1F32GM154449-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ryan Wyatt Mull
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901283

## Citation

> US National Institutes of Health, RePORTER application 10901283, Identification and Biosynthesis of Dehydrated Nonribosomal Peptides from Streptomyces (1F32GM154449-01). Retrieved via AI Analytics 2026-06-07 from https://api.ai-analytics.org/grant/nih/10901283. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*