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Abstract
The mechanisms underlying resistance of the Chagas disease parasite, Trypanosoma cruzi, to current therapies are not well understood, including the role of metabolic heterogeneity. We found that limiting exogenous glutamine protects actively dividing amastigotes from ergosterol biosynthesis inhibitors (azoles), independent of parasite growth rate. The antiparasitic properties of azoles are derived from inhibition of lanosterol 14α-demethylase (CYP51) in the endogenous sterol synthesis pathway. We find that carbons from 13C-glutamine feed into amastigote sterols and into metabolic intermediates that accumulate upon CYP51 inhibition. Incorporation of 13C-glutamine into endogenously synthesized sterols is increased with BPTES treatment, an inhibitor of host glutamine metabolism that sensitizes amastigotes to azoles. Similarly, amastigotes are re-sensitized to azoles following addition of metabolites upstream of CYP51, raising the possibility that flux through the sterol synthesis pathway is a determinant of sensitivity to azoles and highlighting the potential role for metabolic heterogeneity in recalcitrant T. cruzi infection.
Highlights
The goal for treatment of infectious diseases caused by pathogenic bacteria or parasites is to eliminate the pathogenic microorganism from the infected host
To begin to address this prospect, we sought to determine if variable growth conditions known to modulate the proliferative activity of intracellular T. cruzi amastigotes (Dumoulin and Burleigh, 2018) impact the susceptibility of T. cruzi amastigotes to trypanocidal drugs
Dose-response curves for inhibition of intracellular amastigote growth were generated for benznidazole, the first-line therapy for Chagas disease (Bern et al, 2007) and ketoconazole, an azole inhibitor of trypanosome sterol synthesis (Lepesheva et al, 2011), as outlined (Figure 1—figure supplement 1)
Summary
The goal for treatment of infectious diseases caused by pathogenic bacteria or parasites is to eliminate the pathogenic microorganism from the infected host. Standard in vitro inhibitory activity of a candidate compound can be confounded by altered pathogen metabolism due to growth media composition (Hicks et al, 2018; Pethe et al, 2010) and an understanding of these interactions can potentiate treatment (Vestergaard et al, 2017). These complex interactions are best understood in cases of bacterial pathogenesis, but recently, similar trends are apparent in eukaryotic pathogens (Dumont et al, 2019; McLean and Jacobs-Lorena, 2017; Murithi et al, 2020). We show that glutamine metabolism modulates the ability of azoles to eliminate intracellular T. cruzi amastigotes, independent of growth rate
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