Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum

Michael B. Reed, Kevin J. Saliba, Sonia R. Caruana, Kiaran Kirk and Alan F. Cowman ()
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Michael B. Reed: The Walter and Eliza Hall Institute of Medical Research
Kevin J. Saliba: Faculty of Science, Australian National University
Sonia R. Caruana: The Walter and Eliza Hall Institute of Medical Research
Kiaran Kirk: Faculty of Science, Australian National University
Alan F. Cowman: The Walter and Eliza Hall Institute of Medical Research

Nature, 2000, vol. 403, issue 6772, 906-909

Abstract: Abstract Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance1; Pgh1 has also been implicated in resistance to mefloquine and halofantrine2,3,4,5. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine6. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.

Date: 2000
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DOI: 10.1038/35002615

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