Two mutations in the multidrug-resistance gene homologue of Plasmodium falciparum, pfmdr1, are not useful predictors of in-vivo or in-vitro chloroquine resistance in southern Africa

McCutcheon, Keir; Freese, Janet A.; Frean, John; Sharp, Brian; Markus, Miles B.

doi:10.1016/s0035-9203(99)90029-9

Cited by 26 publications

(15 citation statements)

References 17 publications

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“…Interestingly, for the panel of isolates studied here, the 75E mutation had a better predictive value for in vitro chloroquine resistance. By contrast, consistent with previous observations (2,3,16,28) we failed to detect a positive correlation between the pfmdr1 codon 86 polymorphism and in vitro chloroquine phenotype.…”

Section: Discussionsupporting

confidence: 90%

pfcrt Polymorphism and Chloroquine Resistance in Plasmodium falciparum Strains Isolated in Cambodia

Lim

Chy

Ariey

et al. 2003

Antimicrob Agents Chemother

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Plasmodium falciparum chloroquine resistance was first detected in Cambodia in the early sixties. Treatment with chloroquine was abandoned 20 years ago. In vitro chloroquine sensitivity monitoring indicates that all eastern Cambodian isolates were sensitive to chloroquine, whereas most isolates collected from western provinces displayed reduced susceptibility to chloroquine. This indicates that the rate of chloroquine resistance remains high and stable in this region in the absence of chloroquine pressure. Characterization of codons 72 to 78 and 218 to 220 of pfcrt revealed six distinct haplotypes, four of which had never been described. The frequency of each haplotype depended on the geographical origin of the samples. The CVIETIF//ISS haplotype was detected in 92% of western Cambodian isolates and in 11% of isolates collected from the eastern province, where CVMNKIF//ISA and CVIDTIF//ISS predominate. The detection of an intermediate haplotype from a susceptible area with 76T/220A, suggests that acquisition of chloroquine resistance might be a stepwise process, during which accumulation of point mutations modulates the response to chloroquine. The association of the K76T mutation with chloroquine resistance was not clear. The mutation was detected in resistant and susceptible samples, suggesting that additional factors are involved in chloroquine resistance. By contrast, the pfcrt D/N75E mutation was strongly associated with the in vitro chloroquine resistance in Cambodian isolates. The N86 allelic form of pfmdr1 was detected in all isolates, consistent with a poor association with resistance to chloroquine. This indicates that in vitro resistance to chloroquine was associated with accumulation of point mutations in pfcrt.

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Section: Discussionsupporting

confidence: 90%

pfcrt Polymorphism and Chloroquine Resistance in Plasmodium falciparum Strains Isolated in Cambodia

Lim

Chy

Ariey

et al. 2003

Antimicrob Agents Chemother

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“…Some previous studies have confirmed the association between the N86Y mutation in the pfmdr-1 gene and the CQ response (Póvoa et al 1998, Volkman & Wirth 1998). However, many other studies have reported a negative correlation between the N86Y mutation and the CQ response (Wellems et al 1990, Basco et al 1996, Basco & Ringwald 1997, McCutcheon et al 1999). The high prevalence of both the mutations K76T and N86Y in Odisha might be due to the high selection pressure of CQ-resistance, which is a matter of great concern to public health.…”

Section: Discussionmentioning

confidence: 97%

Sequence analysis of coding DNA fragments of pfcrt and pfmdr-1 genes in Plasmodium falciparum isolates from Odisha, India

Sutar

Gupta

Ranjit

et al. 2011

Mem. Inst. Oswaldo Cruz

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“…Subsequent field isolate‐based studies on the relationship between pfmdr1 3′ coding point mutations and parasite susceptibility to quinoline‐based compounds have generated considerable controversy and conflicting results. These have tended to focus on CQR, and in the case of Asian and African parasites an association was observed in some studies (Flueck et al ., 2000; Nagesha et al ., 2001; Pickard et al ., 2003) but not the majority (Wilson et al ., 1993; Chaiyaroj et al ., 1999; McCutcheon et al ., 1999; Basco and Ringwald, 2002). Similar studies in South America have detected a much higher prevalence of these point mutations (particularly S1034C and N1042D), which possibly could contribute to the nearly ubiquitous presence of CQR in this continent (Povoa et al ., 1998; Zalis et al ., 1998; Pillai et al ., 2003; Huaman et al ., 2004).…”

Section: Introductionmentioning

confidence: 99%

pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum

Sidhu

Gaw

Fidock

2005

Molecular Microbiology

326

360

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SummaryThe emergence and spread of multidrug resistant Plasmodium falciparum has severely limited the therapeutic options for the treatment of malaria. With ever-increasing failure rates associated with chloroquine or sulphadoxine-pyrimethamine treatment, attention has turned to the few alternatives, which include quinine and mefloquine. Here, we have investigated the role of pfmdr1 3 ¢ ¢ ¢ ¢ coding region point mutations in antimalarial drug susceptibility by allelic exchange in the GC03 and 3BA6 parasite lines. Results with pfmdr1 -recombinant clones indicate a significant role for the N1042D mutation in contributing to resistance to quinine and its diastereomer quinidine. The triple mutations S1034C/N1042D/D1246Y, highly prevalent in South America, were also found to enhance parasite susceptibility to mefloquine, halofantrine and artemisinin. pfmdr1 3 ¢ ¢ ¢ ¢ mutations showed minimal effect on P. falciparum resistance to chloroquine or its metabolite mono-desethylchloroquine in these parasite lines, in contrast to previously published results obtained with 7G8 parasites. This study supports the hypothesis that pfmdr1 3 ¢ ¢ ¢ ¢ point mutations can significantly affect parasite susceptibility to a wide range of antimalarials in a strain-specific manner that depends on the parasite genetic background.

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Two mutations in the multidrug-resistance gene homologue of Plasmodium falciparum, pfmdr1, are not useful predictors of in-vivo or in-vitro chloroquine resistance in southern Africa

Cited by 26 publications

References 17 publications

pfcrt Polymorphism and Chloroquine Resistance in Plasmodium falciparum Strains Isolated in Cambodia

pfcrt Polymorphism and Chloroquine Resistance in Plasmodium falciparum Strains Isolated in Cambodia

Sequence analysis of coding DNA fragments of pfcrt and pfmdr-1 genes in Plasmodium falciparum isolates from Odisha, India

pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum

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