ASMicro 2015* Mechanisms underlying patterns of inverse drug resistance in the human malaria parasite Plasmodium falciparum (#106)
The global campaign to control malaria is under serious threat from the emergence and spread of Plasmodium falciparum parasites that are resistant to the existing antimalarials. However, it is becoming increasingly evident that parasites resistant to the former ‘wonder drug’ chloroquine (CQ) exhibit hypersensitivity to a diverse range of compounds, including the frontline antimalarial lumefantrine, the antiviral drug amantadine (AMT), and a number of antibiotics. Moreover, a decrease in the parasite’s susceptibility to these drugs is accompanied by a return to CQ-sensitive status. The molecular mechanism(s) underpinning these patterns of inverse drug resistance have not been elucidated, but it is clear that mutations in the parasite’s ‘chloroquine resistance transporter’ (PfCRT) play a key role. We have established a robust system for the functional characterization of PfCRT in Xenopus laevis oocytes (Martin et al. Science, 2009), which we employed to show that a range of different CQ resistance-conferring forms of PfCRT mediate the efflux of CQ from the parasite’s digestive vacuole (i.e., away from the drug’s site of accumulation and action), whereas the wild-type protein lacks this activity (Summers et al. PNAS, 2014). Using this system, we have examined interactions between PfCRT and drugs that possess activities that are inversely-correlated with that of CQ. Our data indicate that there are at least two different mechanisms by which PfCRT can increase the potency of certain drugs against CQ-resistant parasites. This work, and the potential for designing combination therapies that pair antimalarials with opposing selection forces, will be discussed.
