# Biosynthesis of antifungal nucleoside antibiotics

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $339,735

## Abstract

Project Summary/Abstract
Peptidyl nucleosides (PNs) are naturally occurring antifungal agents active against multiple pathogenic fungi
such as the causal agent of “Valley Fever”. They also exhibit potent synergistic effects with clinically approved
antifungal drugs. Our long-term goal is to provide a comprehensive understanding of both the biosynthesis of
PNs and their mode of action. The current application focuses on the biosynthesis of PNs. Understanding PN
biosynthetic pathways will provide a basis for creating structurally diverse PN analogs through engineered
biosynthesis, semi synthesis and genome mining. In the previous funding cycle, we found that PNs are
biosynthesized through cryptic phosphorylation and carbohydrate tailoring by oxidative C-C bond cleavage. On
the basis of these findings, in this application, we will perform functional and mechanistic characterization of the
biosynthetic enzymes to provide the foundation for genome mining discovery of novel nucleoside natural
products and chemoenzymatic synthesis of unnatural PNs. In Aim 1, the mechanism of removal of cryptic
phosphorylation and the generality of cryptic phosphorylation in other nucleoside biosynthesis pathways will be
investigated. In Aim 2, the radical mediated divergent biosynthesis of nucleoside natural products will be
investigated by studying the mechanism of oxidative C-C bond cleavage and genome mining characterization of
homologous enzymes. In Aim 3, the mechanism of amide ligation by NikS/PolG enzymes will be characterized,
and their potentials for use in the chemoenzymatic preparation of PNs will be investigated. The proposed
research is significant because it will provide a basis for the future biosynthetic and chemoenzymatic generation
of novel therapeutic PNs as well as genome mining discovery of novel antifungal nucleoside natural products.

## Key facts

- **NIH application ID:** 10470406
- **Project number:** 5R01GM115729-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Kenichi Yokoyama
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,735
- **Award type:** 5
- **Project period:** 2015-07-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470406

## Citation

> US National Institutes of Health, RePORTER application 10470406, Biosynthesis of antifungal nucleoside antibiotics (5R01GM115729-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470406. Licensed CC0.

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