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Glutamine metabolism modulates azole susceptibility in Trypanosoma cruzi amastigotes

Peter C Dumoulin1, Joshua Vollrath1,2, Sheena Shah Tomko1

  • 1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.

Elife
|December 1, 2020
PubMed

Insights

Limiting glutamine protects Chagas disease parasites (Trypanosoma cruzi) from azole drugs by altering sterol synthesis. Metabolic heterogeneity influences parasite drug resistance.

Area of Science:

  • Parasitology
  • Molecular Biology
  • Drug Resistance Mechanisms

Background:

  • Chagas disease, caused by *Trypanosoma cruzi*, poses a significant health burden.
  • Current therapies for Chagas disease have limitations, and mechanisms of parasite resistance are poorly understood.
  • Metabolic heterogeneity may play a role in *T. cruzi* drug resistance.

Purpose of the Study:

  • To investigate the role of metabolic heterogeneity in *Trypanosoma cruzi* resistance to ergosterol biosynthesis inhibitors (azoles).
  • To elucidate the metabolic pathways involved in parasite survival and drug sensitivity.

Main Methods:

  • Utilized 13C-labeled glutamine to trace metabolic flux in *T. cruzi* amastigotes.
  • Assessed parasite response to azole drugs under varying glutamine availability.
  • Investigated the impact of BPTES (glutamine metabolism inhibitor) and upstream sterol synthesis metabolites on azole sensitivity.

Main Results:

  • Limiting exogenous glutamine conferred resistance to azoles in actively dividing amastigotes, independent of growth rate.
  • 13C-glutamine carbons were incorporated into amastigote sterols and accumulated metabolic intermediates upon CYP51 inhibition.
  • BPTES treatment increased 13C-glutamine incorporation into sterols and sensitized amastigotes to azoles.
  • Addition of metabolites upstream of CYP51 re-sensitized amastigotes to azoles.

Conclusions:

  • Flux through the sterol biosynthesis pathway is a key determinant of *T. cruzi* sensitivity to azole drugs.
  • Metabolic heterogeneity, particularly involving glutamine metabolism, contributes to parasite resistance.
  • Targeting host or parasite metabolic pathways could offer new strategies against recalcitrant Chagas disease infections.
Keywords:
Trypanosoma cruzidrug resistanceinfectious diseasemetabolismmicrobiologysterol biosynthesis

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