Fig 7. Roles of PfMDR1 and PfCRT in the parasite’s susceptibility to lumefantrine, mefloquine, and chloroquine.

Mechanistic explanations for how polymorphisms in pfmdr1 and pfcrt alter the parasite’s response to lumefantrine and mefloquine (a) and chloroquine (b). Lumefantrine, mefloquine, and chloroquine are weak bases that enter the DV via 2 main routes: (1) simple diffusion of the neutral species across the membrane and subsequent protonation within the acidic DV lumen; and (2) ATP-driven import via PfMDR1. Wild-type PfMDR1 has a high capacity for drug transport and this activity, together with the inability of wild-type PfCRT to efflux lumefantrine, mefloquine, or chloroquine from the DV, causes these drugs to sequester within the DV. Overexpression of PfMDR1 results in a further increase in the rate of drug transport from the cytosol into the DV and thus greater accumulation of lumefantrine, mefloquine, and chloroquine in the DV (as well as concomitant reductions in their cytosolic concentrations). In parasites carrying a mutant PfMDR1 isoform (and/or only one pfmdr1 copy) as well as a mutant isoform of PfCRT, there is a marked reduction in the DV accumulation of lumefantrine, mefloquine, and chloroquine as a result of (1) a decrease in the rate of drug import via PfMDR1; and (2) the PfCRT-mediated efflux of drugs from the DV back into the cytosol. The reduction in the concentration of chloroquine at its primary site of action allows the parasite to evade its killing effects, thereby causing chloroquine resistance. On the other hand, the concomitant increases in the cytosolic drug concentrations render these parasites more sensitive to lumefantrine and mefloquine, indicating that the primary targets of both drugs are located outside of the DV. CQ, chloroquine; DV, digestive vacuole; LM, lumefantrine; MQ, mefloquine; PfCRT, Plasmodium falciparum chloroquine resistance transporter; PfMDR1, Plasmodium falciparum multidrug resistance protein 1.