# Exploring metabolic resistance to small molecule inhibitors in Trypanosoma cruzi

> **NIH NIH R21** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2020 · $199,375

## Abstract

Project Summary
Chronic infections with the protozoan parasite and causative agent of human Chagas disease, Trypanosoma
cruzi, are notoriously challenging to treat. The available drugs often fail to achieve sterilizing cure under the
current treatment regimens. Ergosterol biosynthesis inhibitors (EBIs) also failed to clear parasites from chronic
patients in recent clinical trials. These findings, coupled with results from animal models showing selective
survival of T. cruzi in certain tissues after EBI treatment, raise the possibility that characteristics of the local
tissue environment impact susceptibility of intracellular parasites to trypanocidal drugs. In the cancer field, it is
well-established that differences in the metabolic state of tumor cells, due to heterogeneity of cell populations
and their environments, can lead to `metabolic resistance' and treatment failure. Because T. cruzi colonizes
diverse tissues in the mammalian host, each with its own unique metabolic signature, we hypothesize that
comparable mechanisms of metabolic resistance to anti-trypanosomal drugs may contribute to failure to
achieve parasitological cure in chronic T. cruzi infection. Consistent with this idea, preliminary studies show
that a single change in the composition of the cell culture medium protects intracellular T. cruzi amastigotes
from the lethal effects of EBIs. The goals of this proposed study are to determine the role of glutamine
metabolism in sensitizing T. cruzi amastigotes to EBIs using a combination of molecular genetic and
biochemical approaches (Aim1) and to determine the broader impact of metabolic environment on the efficacy
of the next generation of candidate anti-trypanosomals by re-screening the ChagasBox collection of T. cruzi
growth inhibitors under diverse conditions (Aim 2). As a case study for metabolic resistance, the proposed
study addresses a critical gap in our understanding of how diverse cellular and metabolic environments, such
as those encountered by T. cruzi in vivo, impact the ability to effectively eliminate this pathogen from infected
hosts, a key current challenge in the treatment of Chagas disease.

## Key facts

- **NIH application ID:** 9948575
- **Project number:** 5R21AI146815-02
- **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:** 2020
- **Award amount:** $199,375
- **Award type:** 5
- **Project period:** 2019-06-10 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948575

## Citation

> US National Institutes of Health, RePORTER application 9948575, Exploring metabolic resistance to small molecule inhibitors in Trypanosoma cruzi (5R21AI146815-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9948575. Licensed CC0.

---

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