Drug resistance in the human malaria parasite

The quinoline drug chloroquine served as the frontline treatment for malaria from the mid 1940s to the 1990s, by which time the emergence and spread of chloroqune-resistant parasites had rendered the drug ineffective in most endemic regions. The non-quinoline antimalarials deployed to replace chloroquine have by comparison suffered short life spans.

Chloroquine-resistant parasites accumulate much less chloroquine than do sensitive parasites, and this difference is attributed primarily to small changes in a single protein, the “chloroquine resistance transporter” (PfCRT). Furthermore, mutations in this protein also modulate the parasite’s susceptibility to a number of other clinically important drugs. However the mechanism by which mutant PfCRT confers reduced chloroquine accumulation, and hence chloroquine resistance had, until recently, been unclear. We established a novel and robust system for the expression of PfCRT in unfertilized frog eggs (Xenopus laevis oocytes) and shown that the resistance-conferring form of the protein possesses significant capacity for transporting chloroquine away from its site of action, whereas the wild-type protein does not (Martin et al., Science 2009). We are currently using the PfCRT expression system to explore a number of important aspects of this protein including:

  • the kinetics of drug transport via mutant PfCRT and of its inhibition by 'resistance reversers' such as verapamil, chlorpheniramine, and saquinavir;
  • the ability of mutant PfCRT to transport other antimalarial drugs (e.g., quinine, piperaquine, amodiaquine, quinacrine, etc);
  • the effect of different resistance-conferring mutations on the capacity of PfCRT for drug transport and the mutational pathways by which this transport activity is likely to have evolved;
  • fundamental investigations into the structure-function of PfCRT, such as whether it functions as an oligomer and the role of putative protein-protein interaction motifs; and
  • the normal function and physiological role of the protein.

Papers from this project:




Aspects of this work are being carried out in collaboration with Doctor Adele Lehane (ANU), Dr Don Van Schalkwyk (London School of Hygiene & Tropical Medicine), Professor Michael Lanzer (University of Heidelberg, Germany), and Dr Simon Cobbold and Professor Malcolm McConville (Bio21 Institute, University of Melbourne).