Wednesday, August 22, 2007

Artemisinin resistant mutants of Toxo have altered calcium homeostasis

Antimicrob Agents Chemother. 2007 Aug 13; [Epub ahead of print]

Artemisinin resistant mutants of Toxoplasma gondii have altered calcium homeostasis

Nagamune K, Moreno SN, Sibley LD

Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, 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, GA 30602.

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 Ca(2+) ATPase (SERCA) in malaria. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and hence generally not used therapeutically to treat toxoplasmosis. To explore the mechanism of action, we generated chemically derived mutants of T. gondii that were resistant to growth inhibition by this compound in vitro. Three artemisinin resistant (ART(R)) mutant clones were obtained that differed in their sensitivities in vitro by 3-5 fold vs. wild type parasites. 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 expression differences in SERCA, or other putative targets such as MDR or translationally-controlled tumor protein (TCTP). 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 induced secretion 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.

PMID: 17698618 [PubMed - as supplied by publisher]

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