Alkyl-lysophospholipid resistance in multi drug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator

Drug resistance has emerged as a major impediment in the treatment of leish maniasis. Alkyl-lysophospholipids (ALP), originally developed as anticancer drugs, are considered to be the most promising antileishmanial agents. In order to anticipate probable clinical failure in the near future, we have i nvestigated possible mechanisms of resistance to these drugs in Leishmania spp. The results presented here support the involvement of a member of the ATP-binding cassette (ABC) superfamily, the Leishmania P-glyco protein-like transporter, in the resistance to ALP. (i) First, a multidrug resistance ( MDR) Leishmania tropica line overexpressing a P-glycoprotein-like transport er displays significant cross-resistance to the ALP miltefosine and edelfos ine, with resistant indices of 9.2- and 7.1-fold, respectively. (ii) Reduce d expression of P-glycoprotein in the MDR line correlates with a significan t decrease in ALP resistance. (iii) The ALP were able to modulate the P-gly coprotein-mediated resistance to daunomycin in the MDR line. (iv) We have f ound a new Inhibitor of this transporter, the sesquiterpene C-3, that compl etely sensitizes MDR parasites to ALP. (v) Finally, the MDR line exhibits a lower accumulation than the wild-type line of bodipy-C-5-PC, a fluorescent analogue of phosphatidylcholine that has a structure resembling that of ed elfosine. Also, C-3 significantly increases the accumulation of the fluores cent analogue to levels similar to those of wild-type parasites. The involv ement of the Leishmania P-glycoprotein-like transporter in resistance to dr ugs used in the treatment of leishmaniasis also supports the importance of developing new specific inhibitors of this ABC transporter.