Increased Glycolytic ATP Synthesis Is Associated with Tafenoquine Resistance inLeishmania major
ABSTRACTTafenoquine (TFQ), an 8-aminoquinoline used to treat and preventPlasmodiuminfections, could represent an alternative therapy for leishmaniasis. Indeed, TFQ has shown significant leishmanicidal activity bothin vitroandin vivo, where it targetsLeishmaniamitochondria and activates a final apoptosis-like process. In order not to jeopardize the life span of this potential antileishmania drug, it is important to determine the likelihood thatLeishmaniawill develop resistance to TFQ and the mechanisms of resistance induced. To address this issue, a TFQ-resistantLeishmania majorpromastigote line (R4) was selected. This resistance, which is unstable in a drug-free medium (revertant line), was maintained in intramacrophage amastigote forms, and R4 promastigotes were found to be cross-resistant to other 8-aminoquinolines. A decreased TFQ uptake, which is probably associated with an alkalinization of the intracellular pH rather than drug efflux, was observed for both the R4 and revertant lines. TFQ induces a decrease in ATP synthesis in allLeishmanialines, although total ATP levels were maintained at higher values in R4 parasites. In contrast, ATP synthesis by glycolysis was significantly increased in R4 parasites, whereas mitochondrial ATP synthesis was similar to that in wild-type parasites. We therefore conclude that increased glycolytic ATP synthesis is the main mechanism underlying TFQ resistance inLeishmania.