Figure 6. Proposed roles for PfMDR1 and PfCRT in the P. falciparum response to CQ and LMF.

(a) CQ (a weak base) and the hydrophobic drug LMF are thought to enter the DV via simple diffusion across the membrane. Within the DV, CQ is thought to trigger parasite killing by binding to reactive haem moieties and preventing their biomineralization into chemically inert haemozoin crystals⁶⁷. LMF also shows moderate binding to haem²; however, its main site of action is suspected to be outside of the DV. It is thought that PfCRT facilitates the efflux of drugs from the DV, and that PfMDR1 transports drugs into the DV³,⁶⁸. (b–e) Point mutations in these transporters are known to differentially impact parasite susceptibility to CQ and LMF. The N86Y mutation is thought to ablate PfMDR1-mediated CQ transport activity²², but the resulting reduction in the rate of CQ influx is insufficient to confer CQ resistance in parasites that carry wild-type PfCRT (designated as K76)⁴⁷ (b,c). CQ resistance-conferring isoforms of PfCRT (designated K76T) mediate the efflux of CQ from the DV⁶⁸,⁶⁹,⁷⁰. The reduced rate of CQ influx in PfMDR1 N86Y parasites may further decrease CQ concentrations in the DV and thus augment CQ resistance. However, this effect is only evident in parasites expressing a high-capacity transporter of CQ (for example, GB4 PfCRT)⁴⁷. This is perhaps because the loss of CQ influx via PfMDR1 causes a substantial decrease in the time taken to reach sub-lethal levels of CQ in the DV only when the drug is being extruded from the DV via K76T PfCRT at a relatively high rate. (e) LMF might also be a substrate of PfMDR1 N86 (b,d) and the introduction of N86Y (c,e) might likewise reduce the capacity of PfMDR1 to import LMF into the DV. In this scenario, the heightened susceptibility of CQ-resistant N86Y PfMDR1 parasites to LMF could be due to the increased accumulation of LMF in the cytosol (where its main antimalarial target may be located). The relative sizes of the CQ and LMF text in these panels reflect the predicted distribution of the drugs between the DV and cytosol.