title: Sitamaquine overcomes ABC-mediated resistance to miltefosine and antimony in Leishmania.
abstract: Although oral miltefosine represented an important therapeutic advance in the treatment of leishmaniasis, the appearance of resistance remains a serious threat. LMDR1/LABCB4, a P-glycoprotein-like transporter included in the Leishmania ABC (ATP-binding cassette) family, was the first molecule shown to be involved in experimental miltefosine resistance. LMDR1 pumps drugs out of the parasite, thereby decreasing their intracellular accumulation. Sitamaquine, another promising oral drug for leishmaniasis, is currently in phase 2b clinical trials. The physicochemical features of this drug suggested to us that it could be considered for use as an LMDR1 inhibitor. Indeed, we report herein that nonleishmanicidal concentrations of sitamaquine reverse miltefosine resistance in a multidrug resistance Leishmania tropica line that overexpresses LMDR1. This reversal effect is due to modulation of the LMDR1-mediated efflux of miltefosine. In addition, sitamaquine is not a substrate of LMDR1, as this transporter does not affect sitamaquine accumulation or sensitivity in the parasite. Likewise, we show that ketoconazole, another oral leishmanicidal drug known to interact with ABC transporters, is also able to reverse LMDR1-mediated miltefosine resistance, although with a lower efficiency than sitamaquine. Molecular docking on a three-dimensional homology model of LMDR1 showed different preferential binding sites for each substrate-inhibitor pair, thus explaining this different behavior. Finally, we show that sitamaquine is also able to modulate the antimony resistance mediated by MRPA/LABCC3, another ABC transporter involved in experimental and clinical antimony resistance in this parasite. Taken together, these data suggest that the combination of sitamaquine with miltefosine or antimony could avoid the appearance of resistance mediated by these membrane transporters in Leishmania.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Victoria
authors.forename: Boris I
authors.initials: BI
authors.lastname: Bavchvarov
authors.forename: Iván R
authors.initials: IR
authors.lastname: Torrecillas
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-García
authors.forename: Carmen
authors.initials: C
authors.lastname: López-Martín
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000634:Aminoquinolines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000965:Antimony / Q000494:pharmacology* / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000378:metabolism / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D007654:Ketoconazole / Q000378:metabolism / Q000494:pharmacology; D007895:Leishmania tropica / Q000187:drug effects* / Q000378:metabolism; D007896:Leishmaniasis / Q000188:drug therapy; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding
chemical_list: D018528:ATP-Binding Cassette Transporters; D000634:Aminoquinolines; D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine; D000965:Antimony; D007654:Ketoconazole; C080436:8-aminoquinoline