Abstract
Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance. Here, we provide conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP-Binding Cassette Transporters*
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Alleles
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Amodiaquine / pharmacology
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Animals
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Antimalarials / metabolism
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Antimalarials / pharmacology*
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Artemisinins*
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Chloroquine / metabolism
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Chloroquine / pharmacology*
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Cloning, Molecular
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Drug Resistance / genetics*
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Genes, Protozoan
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Haplotypes
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Mefloquine / pharmacology
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Membrane Proteins / genetics*
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Membrane Proteins / physiology
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Membrane Transport Proteins
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Parasitic Sensitivity Tests
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Phenotype
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Plasmodium falciparum / drug effects*
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Plasmodium falciparum / genetics
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Plasmodium falciparum / metabolism
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Point Mutation*
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Protozoan Proteins / genetics
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Protozoan Proteins / physiology
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Quinine / pharmacology
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Sesquiterpenes / pharmacology
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Transfection
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Verapamil / pharmacology
Substances
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ATP-Binding Cassette Transporters
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Antimalarials
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Artemisinins
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Membrane Proteins
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Membrane Transport Proteins
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PfCRT protein, Plasmodium falciparum
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Protozoan Proteins
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Sesquiterpenes
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mdr gene protein, Plasmodium
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Amodiaquine
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Chloroquine
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artemisinin
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Quinine
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Verapamil
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Mefloquine