# Exploring the potential to improve azole efficacy against Trypanosoma cruzi by targeting glutamine metabolism

> **NIH NIH R21** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2021 · $239,250

## Abstract

PROJECT SUMMARY
Chronic infections with the Chagas disease parasite, Trypanosoma cruzi, are notoriously difficult to treat with the
current drug regimens. The mechanism(s) underlying recalcitrant T. cruzi infection are unknown, but this remains
one of the most pressing problems in the field. Of the potential explanations for drug failure, the role that
heterogeneous metabolic environments might play in drug susceptibility in T. cruzi, has not been explored.
Recently, we discovered a novel link between glutamine metabolism and the trypanocidal action of a group of
azole compounds that target sterol biosynthesis in T. cruzi amastigotes. We find that under conditions of limiting
glutamine availability, intracellular amastigotes survive exposure to lethal concentrations of azoles, including
posaconazole, a drug that failed to clear T. cruzi infection from chronically-infected Chagas patients in clinical
trials. Given evidence that glutamine levels are lowest in the region of the gastrointestinal tract that these
parasites are known to persist and recrudesce following azole treatment, our novel findings may have important
implications for the failure of posaconazole to clear parasite infection in mice and chronic Chagas patients. The
goals of this exploratory R21 proposal are to define the mechanism(s) by which access to exogenous glutamine
modulates azole-dependent killing of intracellular T. cruzi amastigotes and to identify compounds in small
molecule library screens that specifically ablate parasite protection from azoles under conditions of glutamine
restriction in culture. Results from this study have the potential to reveal auxiliary glutamine-sensitive pathways
in the parasite that can be targeted to potentiate the efficacy of azoles in low glutamine settings as well a set of
compounds that will serve as powerful tools for future functional studies.

## Key facts

- **NIH application ID:** 10355041
- **Project number:** 1R21AI166974-01
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** BARBARA A BURLEIGH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $239,250
- **Award type:** 1
- **Project period:** 2021-09-27 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355041

## Citation

> US National Institutes of Health, RePORTER application 10355041, Exploring the potential to improve azole efficacy against Trypanosoma cruzi by targeting glutamine metabolism (1R21AI166974-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10355041. Licensed CC0.

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