# Chemical Biology Studies of the Dynamics and Inhibition of Peptidoglycan Biosynthesis

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $375,579

## Abstract

PROJECT TITLE: Chemical Biology Studies of the Dynamics and Inhibition of Peptidoglycan
Biosynthesis
PROJECT SUMMARY
This MIRA application represents the fusion of two complementary research programs that are, broadly
described, directed at the urgent public health threat posed by antibiotic resistance. Infectious diseases are the
leading cause of death world-wide; unfortunately, antibiotic use provides a strong selective pressure that results
in the selection of strains that are resistant to the antibiotic shortly after its deployment as a therapeutic. While
the selection of bacterial resistance to new antibiotics is inevitable, the development of new antibiotics and/or
the identification of new antibacterial targets is essential to stay ahead in our arms race with bacteria. While
antibacterial agents have been developed against multiple bacterial targets, the best target for antibacterial
development has been, and continues to be, the bacterial cell wall. This MIRA application will capitalize on our
discovery of fluorescent D-amino acids (FDAAs) that have provided unprecedented and heretofore unavailable
tools for the visualization of bacterial cell wall peptidoglycan (PG) dynamics in real time and in live bacterial cells.
Specifically, we propose additional studies to elucidate the details of bacterial cell division and cell separation in
Bacillus subtilis, and we will develop “turn-on” probes that will enable the study of PG synthesis and dynamics
in real-time and in live bacterial cells. We will also continue our effort directed at the synthesis and mechanistic
study of cyclic depsipeptide antibiotics that inhibit PG biosynthesis. Furthermore, we have recently uncovered
data that suggest the cyclic depsipeptides may have a second mechanism of action; specifically, inhibition of
lipid recycling, an essential activity in the PG biosynthesis pathway. The lipid recycling pathway remains to be
clearly elucidated and, when coupled with dual-mode activity that may be inherent to these cyclic depsipeptides
under study, very promising new avenues for the identification of new antibacterial targets and development of
new antibacterial agents are likely to emerge from this research effort.

## Key facts

- **NIH application ID:** 10129978
- **Project number:** 5R35GM136365-02
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Michael S VanNieuwenhze
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,579
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129978

## Citation

> US National Institutes of Health, RePORTER application 10129978, Chemical Biology Studies of the Dynamics and Inhibition of Peptidoglycan Biosynthesis (5R35GM136365-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129978. Licensed CC0.

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