Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from
            <i>Plasmodium vivax</i>

Hastings, Michele D.; Sibley, Carol Hopkins

doi:10.1073/pnas.182295999

Cited by 81 publications

(77 citation statements)

References 53 publications

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“…Although antifolate drugs have not been recommended for treating P. vivax malaria, recent studies suggest that this family of drugs may find a role in future treatment of P. vivax malaria in certain regions. 16,37 In this study, we have analyzed pvdhfr and pvdhps mutations in two P. vivax populations from both temperate zone and subtropical provinces of China. Our study showed …”

Section: Discussionmentioning

confidence: 99%

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Miao

Zhou

Cui

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Abstract. Antifolate resistance in Plasmodium vivax is caused by point mutations in genes encoding dihydrofolate reductase ( pvdhfr ) and dihydropteroate synthase ( pvdhps ). In this study, we used direct sequencing to survey pvdhfr and pvdhps mutations in 122 clinical P. vivax isolates from a central and a southern province of China. For pvdhfr , 36.9% were wild-type, whereas mutations were detected at four codons (57, 58, 61, and 117). The S117N/T mutation was the most prevalent (48.4%), followed by the T61M mutation (18.9%). Six pvdhfr mutant alleles were found, ranging from 37.7% to 0.8%. The dramatically different pvdhfr allele frequencies between the two P. vivax populations might be caused by different drug histories or intrinsic difference between temperate and subtropical strains. In contrast, except polymorphisms within a repeat region, no resistance-conferring mutations were detected in pvdhps . Our result suggests that P. vivax populations in China may be relatively susceptible to sulfadoxine-pyrimethamine.

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Section: Discussionmentioning

confidence: 99%

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Miao

Zhou

Cui

et al. 2010

The American Society of Tropical Medicine and Hygiene

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“…Recent work by Hastings and Sibley (63) suggests that P. vivax may be susceptible to antifolate inhibitors of dihydrofolate reductase (DHFR). DHFR mutations in P. vivax are apparently responsible for the lack of activity among the antifolates.…”

Section: Alternative Therapiesmentioning

confidence: 99%

Chloroquine Resistance inPlasmodium vivax

Baird

2004

Antimicrob Agents Chemother

310

239

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“…However, cloning of the dhfr gene from P. vivax (11) has allowed molecular comparisons of alleles from different regions. Examination of the dhfr locus from only a few locations has already yielded more unique dhfr alleles in vivax populations than the far more extensive examination of P. falciparum has demonstrated (12,23,24,26,27,60). In particular, these studies showed that mutant alleles of the vivax dhfr gene are prevalent in Southeast Asia in areas where there is a long history of extensive S/P use.…”

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Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

Hastings

Maguire

Bangs

et al. 2005

Antimicrob Agents Chemother

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In plasmodia, the dihydrofolate reductase (DHFR) enzyme is the target of the pyrimethamine component of sulfadoxine-pyrimethamine (S/P). Plasmodium vivax infections are not treated intentionally with antifolates. However, outside Africa, coinfections with Plasmodium falciparum and P. vivax are common, and P. vivax infections are often exposed to S/P. Cloning of the P. vivax dhfr gene has allowed molecular comparisons of dhfr alleles from different regions. Examination of the dhfr locus from a few locations has identified a very diverse set of alleles and showed that mutant alleles of the vivax dhfr gene are prevalent in Southeast Asia where S/P has been used extensively. We have surveyed patient isolates from six locations in Indonesia and two locations in Papua New Guinea. We sequenced P. vivax dhfr alleles from 114 patient samples and identified 24 different alleles that differed from the wild type by synonymous and nonsynonymous point mutations, insertions, or deletions. Most importantly, five alleles that carried four or more nonsynonymous mutations were identified. Only one of these highly mutant alleles had been previously observed, and all carried the 57L and 117T mutations. P. vivax cannot be cultured continuously, so we used a yeast assay system to determine in vitro sensitivity to pyrimethamine for a subset of the alleles. Alleles with four nonsynonymous mutations conferred very high levels of resistance to pyrimethamine. This study expands significantly the total number of novel dhfr alleles now identified from P. vivax and provides a foundation for understanding how antifolate resistance arises and spreads in natural P. vivax populations.Plasmodium vivax causes a severe and debilitating febrile illness. This mosquito-borne parasite infects an estimated 80 million people each year and is a prevalent cause of malaria outside sub-Saharan Africa (39). Unfortunately, P. vivax cannot be maintained in continuous culture, so despite its prevalence, the study of vivax has lagged markedly behind that of Plasmodium falciparum. This difference is particularly true with respect to the genetics and epidemiology of drug resistance in P. vivax. Chloroquine has been the first-line antimalarial treatment in most areas of endemicity, but resistance to this drug has virtually eliminated its usefulness against P. falciparum (61, 63, 65) and chloroquine resistance has now been observed with P. vivax as well (1,21,34,45,52,55,58,59). Fansidar, a fixed combination of sulfadoxine and pyrimethamine (S/P), is most often the alternative chosen when chloroquine-resistant P. falciparum parasites render chloroquine ineffective (4). However, S/P has not been recommended for primary therapy of vivax malaria due to the poor clinical efficacy reported when the drug was introduced in the 1950s (13,14,26,49,64,68).In both P. falciparum and P. vivax, the dihydrofolate reductase (DHFR, E.C. 1.5.1.3) enzyme is the therapeutic target of the pyrimethamine component of S/P (12,18,23,26,27,43,44,60). A combination of in vitro analysis of cultu...

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Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax

Cited by 81 publications

References 53 publications

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Chloroquine Resistance inPlasmodium vivax

Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

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