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.