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

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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.