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Review
. 2012 Nov;28(11):504-14.
doi: 10.1016/j.pt.2012.08.002. Epub 2012 Sep 25.

PfCRT and its role in antimalarial drug resistance

Andrea Ecker  1 , Adele M Lehane, Jérôme Clain, David A Fidock
Affiliations
Review

PfCRT and its role in antimalarial drug resistance

Andrea Ecker et al. Trends Parasitol. 2012 Nov.

Abstract

Plasmodium falciparum resistance to chloroquine, the former gold standard antimalarial drug, is mediated primarily by mutant forms of the chloroquine resistance transporter (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes.

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Figures

Figure 1
Figure 1
The appearance and global spread of chloroquine resistance (CQR) in P. falciparum. Resistance is thought to have arisen in at least 6 independent origins (grey circles) and moved progressively as a CQ-driven selective sweep, including from Asia to Africa where it established itself on the East coast in the late 1970s (black circle) [3]. The geographic spread of CQR is overlaid onto a current map of P. falciparum endemicity modeled for 2010 [96]. This map was derived from P. falciparum parasite rate (PfPR) surveys, age standardized to the two to 10 year age range, using model-based geostatistics.
Figure 2
Figure 2
PfCRT polymorphisms and predicted topology. (a) List of major PfCRT haplotypes identified in P. falciparum isolates from malaria-endemic regions. Additional rare mutations observed from patient isolates, as well as ones identified in drug-pressured culture-adapted parasites, are listed in the footnote. (b) Predicted topology showing the location of variant residues. Black and yellow shading indicate residues that vary in field isolates and drug-pressured laboratory lines, respectively. The K76T mutation, central to CQR and used as a molecular marker in endemic areas, is highlighted in red.
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