Abstract
AbstractThe mechanisms underlying resistance of the Chagas disease parasite,Trypanosoma cruzi,to current therapies are not well understood, including the potential role of metabolic heterogeneity in modulating susceptibility of intracellular amastigotes to trypanocidal compounds. 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 from13C-glutamine feed into amastigote sterols and into metabolic intermediates that accumulate upon CYP51 inhibition. Consistent with a model that decreased flux through the sterol biosynthetic pathway is protective for intracellular amastigotes exposed to azoles, we find that amastigotes become re-sensitized to azoles following addition of metabolites upstream of CYP51. Our results highlight the potential role of metabolic heterogeneity in recalcitrantT. cruziinfection, an avenue that is currently underexplored.
Publisher
Cold Spring Harbor Laboratory