Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations.
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TLDR
It is provided 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 chlorquine accumulation.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.read more
Citations
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A molecular marker of artemisinin-resistant Plasmodium falciparum malaria
Frédéric Ariey,Benoit Witkowski,Chanaki Amaratunga,Johann Beghain,Anne-Claire Langlois,Nimol Khim,Saorin Kim,Valentine Duru,Christiane Bouchier,Laurence Ma,Pharath Lim,Rithea Leang,Socheat Duong,Sokunthea Sreng,Seila Suon,Char Meng Chuor,Denis Mey Bout,Sandie Menard,William O. Rogers,Blaise Genton,Thierry Fandeur,Olivo Miotto,Pascal Ringwald,Jacques Le Bras,Antoine Berry,Jean Christophe Barale,Rick M. Fairhurst,Françoise Benoit-Vical,Odile Mercereau-Puijalon,Didier Menard +29 more
TL;DR: Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance.
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Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance
David A. Fidock,Takashi Nomura,Angela K. Talley,Roland A. Cooper,Sergey M. Dzekunov,Michael T. Ferdig,Lyann M. B. Ursos,Amar Bir Singh Sidhu,Bronwen Naudé,Kirk W. Deitsch,Xin-zhuan Su,John C. Wootton,Paul D. Roepe,Thomas E. Wellems +13 more
TL;DR: The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7 that harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America.
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Antimalarial drug discovery: efficacy models for compound screening
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Reemergence of Chloroquine-Sensitive Plasmodium falciparum Malaria after Cessation of Chloroquine Use in Malawi
James G. Kublin,Joseph F. Cortese,Eric Mbindo Njunju,Rabia A G Mukadam,Jack J. Wirima,Peter N. Kazembe,Abdoulaye A. Djimde,Bourema Kouriba,Terrie E. Taylor,Terrie E. Taylor,Christopher V. Plowe +10 more
TL;DR: The reintroduction ofchloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.
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Decreasing pfmdr1 copy number in plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin.
Amar Bir Singh Sidhu,Anne-Catrin Uhlemann,Stephanie G. Valderramos,Juan Carlos Valderramos,Sanjeev Krishna,David A. Fidock +5 more
TL;DR: The importance of pfmdr1 copy number in determining P. falciparum susceptibility to multiple agents currently being used to combat malaria caused by multidrug-resistant parasites is highlighted.
References
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Journal ArticleDOI
Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance
David A. Fidock,Takashi Nomura,Angela K. Talley,Roland A. Cooper,Sergey M. Dzekunov,Michael T. Ferdig,Lyann M. B. Ursos,Amar Bir Singh Sidhu,Bronwen Naudé,Kirk W. Deitsch,Xin-zhuan Su,John C. Wootton,Paul D. Roepe,Thomas E. Wellems +13 more
TL;DR: The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7 that harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America.
Journal ArticleDOI
A molecular marker for chloroquine-resistant falciparum malaria.
Abdoulaye A. Djimde,Ogobara K. Doumbo,Joseph F. Cortese,Kassoum Kayentao,Safi N. Doumbo,Yacouba Diourte,Drissa Coulibaly,Alassane Dicko,Xin-zhuan Su,Takashi Nomura,David A. Fidock,Thomas E. Wellems,Christopher V. Plowe +12 more
TL;DR: This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria, and this mutation can be used as a marker in surveillance forchloroquine-resistant falcIParum malaria.
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Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum.
TL;DR: Direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine is provided, which has important implications for the development and efficacy of future antimalarial agents.
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The structure of malaria pigment β-haematin
TL;DR: The crystal structure of β-haematin determined using simulated annealing techniques to analyse powder diffraction data obtained with synchrotron radiation is reported, which has implications for understanding the action of current antimalarial drugs and possibly for the design of new therapeutic agents.
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Medical need, scientific opportunity and the drive for antimalarial drugs
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