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Antimicrobial Agents and Chemotherapy, July 2004, p. 2370-2378, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2370-2378.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum

Heinrich C. Hoppe,1* Donelly A. van Schalkwyk,2 Ursula I. M. Wiehart,2 Sandra A. Meredith,2 Joanne Egan,2 and Brandon W. Weber2

Division of Pharmacology,2 Institute of Infectious Diseases and Molecular Medicine, University of Cape Town Medical School, Observatory, Cape Town 7925, South Africa1

Received 1 December 2003/ Returned for modification 24 December 2003/ Accepted 16 March 2004

Endocytosis is a fundamental process of eukaryotic cells and fulfills numerous functions, most notably, that of macromolecular nutrient uptake. Malaria parasites invade red blood cells and during their intracellular development endocytose large amounts of host cytoplasm for digestion in a specialized lysosomal compartment, the food vacuole. In the present study we have examined the effects of artemisinin and the quinoline drugs chloroquine and mefloquine on endocytosis in Plasmodium falciparum. By using novel assays we found that mefloquine and artemisinin inhibit endocytosis of macromolecular tracers by up to 85%, while the latter drug also leads to an accumulation of undigested hemoglobin in the parasite. During 5-h incubations, chloroquine inhibited hemoglobin digestion but had no other significant effect on the endocytic pathway of the parasite, as assessed by electron microscopy, the immunofluorescence localization of hemoglobin, and the distribution of fluorescent and biotinylated dextran tracers. By contrast, when chloroquine was added to late ring stage parasites, followed by a 12-h incubation, macromolecule endocytosis was inhibited by more than 40%. Moreover, there is an accumulation of transport vesicles in the parasite cytosol, possibly due to a disruption in vacuole-vesicle fusion. This fusion block is not observed with mefloquine, artemisinin, quinine, or primaquine but is mimicked by the vacuole alkalinizing agents ammonium chloride and monensin. These results are discussed in the light of present theories regarding the mechanisms of action of the antimalarials and highlight the potential use of drugs in manipulating and studying the endocytic pathway of malaria parasites.

* Corresponding author. Mailing address: Division of Pharmacology, University of Cape Town Medical School, Groote Schuur Hospital Old Building, Observatory, Cape Town 7925, South Africa. Phone: 27-21-406 6498. Fax: 27-21-448 1989. E-mail: hhoppe{at}uctgsh1.uct.ac.za.

Antimicrobial Agents and Chemotherapy, July 2004, p. 2370-2378, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2370-2378.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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