Lysosomes and drug resistance in malaria

An increase of susceptibility to the arylamino-alcohols, quinine and mefloquine, and to artemisinin and its metabolite dihydroartemisinin, all highly effective in chloroquine resistance, was associated with transfection of pfcrt from chloroquine-resistant to sensitive clones. This finding indicates that PfCRT has an important role to play, together with PGH-1, in modulating sensitivity to these agents. Sidhu and colleagues point out that this supports the increased use of arylamino-alcohols and artemisinin derivatives in chloroquine-resistance in the field. Differences between sensitivity to quinine and quinidine linked to mutations at pfcrt codon 76 indicate that interactions with PfCRT are sterically as well as hydrophobically restricted, since these diastereomers have very similar hydrophobicities. That the verapamil chemosensitisation phenomenon is also effective for quinine and quinidine in the artificially prepared chloroquine-- resistant clones and differs with different mutations at pfcrt 76 confirms that 4-aminoquinolines, arylamino-alcohols and verapamil interact with the PfCRT protein.