title: Increased glycolytic ATP synthesis is associated with tafenoquine resistance in Leishmania major.
abstract: Tafenoquine (TFQ), an 8-aminoquinoline used to treat and prevent Plasmodium infections, could represent an alternative therapy for leishmaniasis. Indeed, TFQ has shown significant leishmanicidal activity both in vitro and in vivo, where it targets Leishmania mitochondria 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 that Leishmania will develop resistance to TFQ and the mechanisms of resistance induced. To address this issue, a TFQ-resistant Leishmania major promastigote 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 all Leishmania lines, 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 in Leishmania.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Manzano
authors.forename: Luis
authors.initials: L
authors.lastname: Carvalho
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Victoria
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000634:Aminoquinolines / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D006019:Glycolysis; D018320:Leishmania major / Q000187:drug effects* / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000981:Antiprotozoal Agents; C055852:tafenoquine; D000255:Adenosine Triphosphate; D011770:Pyruvate Kinase