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:
- Pulcini S, Staines HM, Lee AH, Shafik SH, Bouyer G, Moore CM, Daley DA, Hoke MJ, Altenhofen LM, Painter HJ, Mu J, Llinás M, Ferguson DJP, Martin RE, Fidock DA, Cooper RA & Krishna S (2015). Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities. Scientific Reports, in press.
- Bellanca S, Summers RL, Meyrath M, Dave A, Nash MN, Dittmer M, Sanchez CP, Stein WD, Martin RE1, and Lanzer M1 (2014). Multiple drugs compete for transport via the P. falciparum chloroquine resistance transporter at distinct but interdependent sites. Journal of Biological Chemistry, 289: 36336-51. [1: Joint senior authors] Open access
- Summers RL1, Dave A1, Dolstra TJ, Bellanca S, Marchetti RV, Nash MN, Richards SN, Goh V, Schenk RL, Stein WD, Kirk K, Sanchez CP, Lanzer M2, and Martin RE2 (2014). Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter. Proceedings of the National Academy of Sciences USA, 111: E1759-67. [1, 2: Equal contributions] Open access
- Summers, RL, Nash MN, and Martin RE (2012). Know your enemy: Understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics. Cellular and Molecular Life Sciences, 69, 1967-95.
- Summers, RL and Martin RE (2010). Functional characteristics of the malaria parasite’s ‘chloroquine resistance transporter’: implications for chemotherapy. Virulence, 1, 304-08. Open access
- Martin RE, Marchetti RV, Cowan AI, Howitt SM, Bröer S, and Kirk K (2009). Chloroquine transport via the malaria parasite’s ‘Chloroquine Resistance Transporter’. Science, 325, 1680-82.
- Martin RE and Kirk K (2004). The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Molecular Biology and Evolution, 21: 1938-49.
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