# Fexinidazole survival genes implicate a novel redox-based mechanism in drug resistance

> **NIH NIH R21** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $199,375

## Abstract

PROJECT SUMMARY
Fexinidazole has emerged as the front-line treatment against African trypanosomiasis, offering the first oral
monotherapy against T. brucei gambiense infections. Because of its current success in African trypanosome
treatment, fexinidazole is actively being investigated as a therapy against American trypanosomiasis (Chagas)
and Leishmaniasis, which currently infect over 15 million people globally. Fexinidazole joined nifurtimox (NECT
combination therapy, HAT) and benznidazole (Chagas disease) as clinically significant nitroaromatic compounds
for the treatment of trypanosomatid infections. Nitroheterocyclic compounds function as prodrugs that require
nitroreductase (NTR) enzymatic activation to generate cytotoxic species that are thought to damage DNA, lipids,
and proteins. Naturally occurring and laboratory resistance and cross-resistance have been documented based
on T. brucei NTR mutants and in RNAi-based knock-down studies, respectively. Fexinidazole is a repurposed
compound whose success in clinical trials enabled rapid approvals with few publications evaluating the drugs
trypanocidal phenotypes, Mechanism of Action (MoA), or potential for drug resistance. Inadequate molecular
understanding of fexinidazole’s MoA and modes of drug resistance represent a significant knowledge gap. To
fill this gap, our state-of-the-art T. brucei Gain-of-Function library was applied to the question of fexinidazole
resistance and preliminary studies identified 11 survival associated ORFs including oxidoreductases, a
peroxidase, dithiol glutaredoxin, and a glutathione S-transferase. Collectively, the identified genes support the
central hypothesis that novel fexinidazole survival genes constitute a redox-based pathway able to promote
nitroaromatic drug resistance with implications for fexinidazole’s MoA. This exploratory proposal will take the
modest risk of investigating genes that promote survival during fexinidazole treatment, toward the high reward
of identifying the drugs molecular targets and drug resistance mechanisms. The Specific Aims are targeted to
answer two significant questions: Are fexinidazole survival ORFs specific to nitroaromatic compounds? and Do
fexinidazole GoF survival genes constitute a redox-based drug resistance pathway? Aim 1 will employ a set of
innovative T. brucei Gain-of-Function genetic screens to determine if the identified fexinidazole survival genes
are (i) specific to fexinidazole resistance, (ii) general to all nitroaromatics, or (iii) broadly associated ROS stress
management. AIM 2 will test the working hypothesis that fexinidazole resistance can arise from a novel redox-
based resistance pathway through unbiased phenotypic analysis of drug resistance and cross-resistance, protein
localization, mitochondrial functionality, cell cycle and DNA synthesis, and ROS and redox. The proposed
research is significant because it will identify genes associated with fexinidazole’s MoA and resistance
mechanisms, filling crit...

## Key facts

- **NIH application ID:** 11230560
- **Project number:** 7R21AI174051-03
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Galadriel Astra Hovel-Miner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $199,375
- **Award type:** 7
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11230560

## Citation

> US National Institutes of Health, RePORTER application 11230560, Fexinidazole survival genes implicate a novel redox-based mechanism in drug resistance (7R21AI174051-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11230560. Licensed CC0.

---

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