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Antimicrobial Agents and Chemotherapy, December 2008, p. 4374-4380, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00666-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Chloroquine Resistance-Conferring Mutations in pfcrt Give Rise to a Chloroquine-Associated H+ Leak from the Malaria Parasite's Digestive Vacuole {triangledown}

Adele M. Lehane and Kiaran Kirk*

Biochemistry and Molecular Biology, School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia

Received 20 May 2008/ Returned for modification 25 August 2008/ Accepted 30 September 2008

Chloroquine resistance in the malaria parasite Plasmodium falciparum is conferred by mutations in the P. falciparum chloroquine resistance transporter (PfCRT). PfCRT localizes to the membrane of the parasite's internal digestive vacuole, an acidic organelle in which chloroquine accumulates to high concentrations and exerts its toxic effect. Mutations in PfCRT are thought to reduce chloroquine accumulation in this organelle. How they do so is the subject of ongoing debate. Recently we have shown that in the presence of chloroquine there is an increased leak of H+ from the digestive vacuole in chloroquine-resistant but not chloroquine-sensitive parasites. Here, using transfectant parasite strains of a single genetic background and differing only in their pfcrt allele, we show that chloroquine resistance-conferring PfCRT mutations are responsible for this chloroquine-associated H+ leak. This is consistent with the hypothesis that the chloroquine resistance-conferring forms of PfCRT mediate the efflux of chloroquine, in association with H+, from the malaria parasite's digestive vacuole.

* Corresponding author. Mailing address: Biochemistry and Molecular Biology, School of Biology, The Australian National University, Canberra ACT 0200, Australia. Phone: 61 2 6125 2284. Fax: 61 2 6125 0313. E-mail: Kiaran.Kirk{at}anu.edu.au

{triangledown} Published ahead of print on 13 October 2008.

Antimicrobial Agents and Chemotherapy, December 2008, p. 4374-4380, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00666-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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