title: Sitamaquine sensitivity in Leishmania species is not mediated by drug accumulation in acidocalcisomes.
abstract: Sitamaquine (WR6026), an 8-aminoquinoline derivative, is a new antileishmanial oral drug. As a lipophilic weak base, it rapidly accumulates in acidic compartments, represented mainly by acidocalcisomes. In this work, we show that the antileishmanial action of sitamaquine is unrelated to its level of accumulation in these acidic vesicles. We have observed significant differences in sitamaquine sensitivity and accumulation between Leishmania species and strains, and interestingly, there is no correlation between them. However, there is a relationship between the levels of accumulation of sitamaquine and acidotropic probes, acidocalcisomes size, and polyphosphate levels. The Leishmania major AP3delta-null mutant line, in which acidocalcisomes are devoid of their usual polyphosphate and proton content, is unable to accumulate sitamaquine; however, both the parental strain and the AP3delta-null mutants showed similar sensitivities to sitamaquine. Our findings provide clear evidence that the antileishmanial action of sitamaquine is unrelated to its accumulation in acidocalcisomes.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Armilla, Granada, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: López-Martín
authors.forename: José María
authors.initials: JM
authors.lastname: Pérez-Victoria
authors.forename: Luis
authors.initials: L
authors.lastname: Carvalho
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
mesh_terms: D000634:Aminoquinolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007891:Leishmania / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D007896:Leishmaniasis / Q000188:drug therapy / Q000469:parasitology; D009154:Mutation; D011122:Polyphosphates / Q000378:metabolism; D013045:Species Specificity
chemical_list: D000634:Aminoquinolines; D000981:Antiprotozoal Agents; D011122:Polyphosphates; C080436:8-aminoquinoline
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