Chloroquine transport via the malaria parasite's chloroquine resistance transporter

Rowena E. Martin; Rosa V. Marchetti; Anna I. Cowan; Susan M. Howitt; Stefan Bröer; Kiaran Kirk

doi:10.1126/science.1175667

Chloroquine transport via the malaria parasite's chloroquine resistance transporter

Rowena E. Martin, Rosa V. Marchetti, Anna I. Cowan, Susan M. Howitt, Stefan Bröer, Kiaran Kirk

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253 Citations (Scopus)

Abstract

The emergence and spread of chloroquine-resistant Plasmodium falciparum malaria parasites has been a disaster for world health. Resistance is conferred by mutations in the Chloroquine Resistance Transporter (PfCRT), an integral membrane protein localized to the parasite's internal digestive vacuole. These mutations result in a marked reduction in the accumulation of chloroquine (CO) by the parasite. However, the mechanism by which this occurs is unclear. We expressed both wild-type and resistant forms of PfCRT at the surface of Xenopus laevis oocytes. The resistant form of PfCRT transported CQ, whereas the wild-type protein did not. CQ transport via the mutant PfCRT was inhibited by CQ analogs and by the resistance-reverser verapamil. Thus, CQ resistance is due to direct transport of the drug via mutant PfCRT.

Original language	English
Pages (from-to)	1680-1682
Number of pages	3
Journal	Science
Volume	325
Issue number	5948
DOIs	https://doi.org/10.1126/science.1175667
Publication status	Published - 2009

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abstract = "The emergence and spread of chloroquine-resistant Plasmodium falciparum malaria parasites has been a disaster for world health. Resistance is conferred by mutations in the Chloroquine Resistance Transporter (PfCRT), an integral membrane protein localized to the parasite's internal digestive vacuole. These mutations result in a marked reduction in the accumulation of chloroquine (CO) by the parasite. However, the mechanism by which this occurs is unclear. We expressed both wild-type and resistant forms of PfCRT at the surface of Xenopus laevis oocytes. The resistant form of PfCRT transported CQ, whereas the wild-type protein did not. CQ transport via the mutant PfCRT was inhibited by CQ analogs and by the resistance-reverser verapamil. Thus, CQ resistance is due to direct transport of the drug via mutant PfCRT.",

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AU - Martin, Rowena E.

AU - Marchetti, Rosa V.

AU - Cowan, Anna I.

AU - Howitt, Susan M.

AU - Bröer, Stefan

AU - Kirk, Kiaran

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AB - The emergence and spread of chloroquine-resistant Plasmodium falciparum malaria parasites has been a disaster for world health. Resistance is conferred by mutations in the Chloroquine Resistance Transporter (PfCRT), an integral membrane protein localized to the parasite's internal digestive vacuole. These mutations result in a marked reduction in the accumulation of chloroquine (CO) by the parasite. However, the mechanism by which this occurs is unclear. We expressed both wild-type and resistant forms of PfCRT at the surface of Xenopus laevis oocytes. The resistant form of PfCRT transported CQ, whereas the wild-type protein did not. CQ transport via the mutant PfCRT was inhibited by CQ analogs and by the resistance-reverser verapamil. Thus, CQ resistance is due to direct transport of the drug via mutant PfCRT.

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Chloroquine transport via the malaria parasite's chloroquine resistance transporter

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