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Artemisinin-Resistant Mutants of Toxoplasma gondii Have Altered Calcium Homeostasis

Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri 63110,¹ Department of Cellular Biology and Center for Tropical and Emerging Global Diseases, Paul D. Coverdell Center for Biomedical and Health Sciences, University of Georgia, Athens, Georgia 30602²

Received 3 May 2007/ Returned for modification 10 July 2007/ Accepted 5 August 2007

Artemisinin is a plant sesquiterpene lactone that has become an important drug for combating malaria, especially in regions where resistance to other drugs is widespread. While the mechanism of action is debated, artemisinin has been reported to inhibit the sarcoplasmic endoplasmic reticulum Ca²⁺ ATPase (SERCA) in the malaria parasite. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and, hence, is generally not used therapeutically to treat toxoplasmosis. To explore the mechanism of action, we generated chemically derived mutants of Toxoplasma gondii that were resistant to growth inhibition by this compound in vitro. Three artemisinin-resistant (ART^r) mutant clones that differed in their sensitivities in vitro by three- to fivefold compared with that of the wild-type parasites were obtained. ART^r mutants were cross-resistant to other derivatives of artemisinin, the most potent of which was artemisone. Resistance was not due to molecular alterations or differences in the expression of SERCA or other putative targets, such as proteins that code for multidrug resistance or translationally controlled tumor protein. ART^r mutants were resistant to the induction of protein secretion from micronemes, a calcium-dependent process that is triggered by artemisinin. ART^r mutants were not cross-resistant to secretion induced by thapsigargin but were more sensitive and were unable to regulate cytoslic calcium following treatment with this compound. These studies implicate calcium homeostasis in the mechanism of action of artemisinins against apicomplexan parasites.

Published ahead of print on 13 August 2007.

This article has been cited by other articles:

• Nagamune, K., Beatty, W. L., Sibley, L. D. (2007). Artemisinin Induces Calcium-Dependent Protein Secretion in the Protozoan Parasite Toxoplasma gondii. Eukaryot Cell 6: 2147-2156 [Abstract] [Full Text]