Fig. 3.

Proposed roles for PfCRT and PfMDR1 in quinoline resistance. a CQ, QN, and MQ are weak bases and therefore accumulate in the acidic environment of the parasite’s digestive vacuole (DV; pH ~5) in their protonated forms (CQH⁺, CQH₂ ²⁺, QNH⁺, and MQH⁺, respectively). PfCRT^CQS does not interact with CQ [49], nor is it thought to interact with QN or MQ [68], whereas wild-type PfMDR1 (b) imports CQ and QN (and possibly MQ) into the DV [76, 77]. Thus, CQ, QN, and MQ are expected to accumulate in the DV of parasites carrying the native forms of these transporters. When present at high concentrations in the DV, CQ kills the parasite by preventing the conversion of the potentially toxic haem monomers into the inert crystal haemozoin. It is not clear whether QN and MQ share this mechanism of action, or if they instead (or in addition) target other processes in the DV and/or the cytosol [24]. Indeed, amplification of wild-type pfmdr1 has been associated with MQ resistance [82, 87–89, 91–94, 211–213]; it is thought that the resulting overexpression of PfMDR1 causes an increase in MQ accumulation within the DV, which in turn leads to a reduction in the concentration of MQ at its putative cytosolic target. c PfCRT^CQR mediates the efflux of CQ (and possibly QN) out of the DV [49, 68]. MQ inhibits transport via PfCRT^CQR [49], but does not appear to be a substrate itself [68]. However, direct measurements of MQ transport via PfCRT are required to confirm this finding. d Certain mutations in PfMDR1 abolish the import of CQ and QN (and possibly MQ) via this protein [76, 77]. Hence, the DV concentrations of CQ, MQ and QN are expected to be reduced when the mutant forms of both proteins are present. In the case of CQ, this results in resistance. By contrast, the decreased levels of MQ in the DV (which may lead to an increase in the cytosolic concentration of MQ) might be expected to increase parasite susceptibility to MQ if the primary target of this drug is cytosolic. Likewise, the effect on QN-susceptibility would depend on whether QN exerts its primary mode of action within the DV or cytosol. Alternatively (or in addition), MQ and QN may inhibit PfCRT^CQR (e) and/or PfMDR1 (f), and thereby exert part of their antimalarial effect by blocking the physiological functions of these transporters [49, 68, 75, 76, 89]. Several resistance-reversers (RR) have been shown to inhibit PfCRT^CQR, and the ability to block this form of the protein may underlie the observed increase in the intrinsic antiplasmodial activities of RRs in CQR versus CQS parasites [56, 65, 69]. Black and green lines indicate transport pathways and red lines denote modes of antimalarial action. Pathways and modes of action that have not been directly demonstrated or characterised are shown as dashed lines