# Synthesis and Chemical Biology of Thiopeptide Antibiotics

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2023 · $302,521

## Abstract

PROJECT SUMMARY/ABSTRACT
Antibiotics have transformed the human health and disease landscape. However, the use and
misuse of such antimicrobial drugs accelerate the emergence of bacterial strains resistant
against antibiotics, so that standard treatment options eventually become ineffective. In light of
these critical needs, thiopeptides have emerged as a promising platform for the discovery of
new therapeutic leads. In Aim 1, we will develop and optimize the preparation of 26-membered
thiopeptides by inventing a new cyclodehydration methods to facilitate the synthetic campaign.
The methods established in this aim will be validated in the context of representative
azole/azoline-containing antimicrobial peptides. In Aim 2, we will optimize a streamlined
synthesis of 35-membered thiopeptides by integrating Mo-catalyzed cyclodehydrations and site-
selective Dha mutations. These findings will unlock the translational potential of a previously
unexplored class of potent antibiotics. In Aim 3, we will develop an automated platform for
rational thiopeptide design and modifications, and integrate it with microbiological, biophysical,
and computational studies to generate promising leads suitable for pre-clinical and clinical
investigations. Successful realization of the abovementioned aims will establish innovative tools
for the synthesis of thiopeptides and other bioactive macrocyclic peptides. Because of the
importance of azol(in)es as the key structural elements in bioactive natural products of
biomedical relevance, the discoveries of this study will have a transformative impact on the
development of new therapies.

## Key facts

- **NIH application ID:** 10557848
- **Project number:** 5R01GM138682-03
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Maciej Walczak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $302,521
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10557848

## Citation

> US National Institutes of Health, RePORTER application 10557848, Synthesis and Chemical Biology of Thiopeptide Antibiotics (5R01GM138682-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10557848. Licensed CC0.

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