# Novel gyrase inhibitors targeting Mycobacterium tuberculosis

> **NIH NIH R21** · FLORIDA INTERNATIONAL UNIVERSITY · 2024 · $186,265

## Abstract

PROJECT SUMMARY
This R21 project is designed to determine structure activity relationships (SARs) of a particular chemotype of
4-(1-methylimidazo[1,2-a]pyridine-1-ium (aka CPD229 and analogs), new antimycobacterial gyrase inhibitors
discovered in our recent HTS campaign targeting bacterial DNA gyrase funded by an NIAID grant
1R21AI125973. We will also improve their Mycobacterium tuberculosis (Mtb) whole cell potency and
pharmacological properties. Additionally, we will determine the mechanism of action (MoA) of these new
gyrase inhibitors both in vitro using purified Mtb gyrase and in vivo within Mtb. DNA gyrase, an essential
enzyme to Mtb, is an excellent and validated target for discovering and developing new antibiotics to treat
MDR-TB. Fluoroquinolones (FQs), one of the most important and prescribed antibiotics, target bacterial DNA
gyrase. FQs are widely used as anti-TB drugs, usually as the second-line antibiotics for MDR-TB patients.
However, FQ-resistant Mtb strains have been discovered threatening the utility of FQ for TB treatment. Certain
FQs also have serious side effects. These newly identified antimycobacterial gyrase inhibitors, structurally
distinct from FQs, provide promising starting points for development and optimization of novel antibiotics that
should yield effective therapeutics capable of overcoming FQ-resistance and effectively treating MDR-TB.
Success in these proposed studies would provide potent non-FQ antimycobacterial gyrase inhibitors for the
development of new antibiotics/therapy for the global public health problem of multi-drug resistant TB.

## Key facts

- **NIH application ID:** 10843242
- **Project number:** 5R21AI178134-02
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Fenfei Leng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $186,265
- **Award type:** 5
- **Project period:** 2023-05-17 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843242

## Citation

> US National Institutes of Health, RePORTER application 10843242, Novel gyrase inhibitors targeting Mycobacterium tuberculosis (5R21AI178134-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10843242. Licensed CC0.

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