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Antimicrobial Agents and Chemotherapy, February 2000, p. 344-347, Vol. 44, No. 2
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mechanisms of Artemisinin Resistance in the Rodent Malaria Pathogen Plasmodium yoelii

Daniel J. Walker,1 Jessica L. Pitsch,1 Michael M. Peng,1 Brian L. Robinson,2 Wallace Peters,2 Jamaree Bhisutthibhan,1 and Steven R. Meshnick1,*

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan 48109,1 and Tropical Parasitic Diseases Unit, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, United Kingdom2

Received 8 February 1999/Returned for modification 28 May 1999/Accepted 23 November 1999

Artemisinin and its derivatives are important new antimalarials which are now used widely in Southeast Asia. Clinically relevant artemisinin resistance has not yet been reported but is likely to occur. In order to understand how the malaria parasite might become resistant to this drug, we studied artemisinin resistance in the murine malaria parasite Plasmodium yoelii. The artemisinin-resistant strain (ART), which is approximately fourfold less sensitive to artemisinin than the sensitive NS strain, accumulated 43% less radiolabeled drug in vitro (P < 0.01). Within the parasite, the drug appeared to react with the same parasite proteins in both strains. The translationally controlled tumor protein, one of the artemisinin target proteins, did not differ between the strains. No DNA sequence difference was found, but the resistant strain was found to express 2.5-fold-more protein than the sensitive strain (P < 0.01). Thus, the phenotype of artemisinin resistance in P. yoelii appears to be multifactorial.

* Corresponding author. Mailing address: Department of Epidemiology, School of Public Health I, University of Michigan, Ann Arbor, MI 48109. Phone: (734) 647-2406. Fax: (734) 764-3192. E-mail: meshnick{at}umich.edu.

Antimicrobial Agents and Chemotherapy, February 2000, p. 344-347, Vol. 44, No. 2
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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