Mutations in the antifolate-resistance-associated genes dihydrofolate reductase and dihydropteroate synthase in Plasmodium vivax isolates from malaria-endemic countries.

Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea.
The American journal of tropical medicine and hygiene (Impact Factor: 2.53). 09/2010; 83(3):474-9. DOI: 10.4269/ajtmh.2010.10-0004
Source: PubMed

ABSTRACT Parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) are known target enzymes of antifolate drugs used for the treatment and prophylaxis of persons with malaria. We sequenced the Plasmodium vivax dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) genes to examine the prevalence and extent of point mutations in isolates from malaria-endemic countries. Double mutations (S58R and S117N) or quadruple mutations (F57L/I, S58R, T61M, and S117T) in the pvdhfr gene were found in isolates from Thailand (96.4%) and Myanmar (71.4%), but in only one isolate (1.0%) from Korea, where sulfadoxine-pyrimethamine has never been used. The pvdhfr point mutations correlated strongly with the pvdhps point mutations and ranged from single to triple mutations (S382A, A383G, and A553G), among isolates from Thailand, Myanmar, and Korea. These findings suggests that the prevalence of mutations in pvdhfr and pvdhps in P. vivax isolates from different malaria-endemic countries is associated with selection pressure imposed by sulfadoxine-pyrimethamine.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance of Plasmodium spp. to anti-malarial drugs is the primary obstacle in the fight against malaria, and molecular markers for the drug resistance have been applied as an adjunct in the surveillance of the resistance. In this study, we investigated the prevalence of mutations in pvmdr1, pvcrt-o, pvdhfr, and pvdhps genes in temperate-zone P. vivax parasites from central China. A total of 26 isolates were selected, including 8 which were previously shown to have a lower susceptibility to chloroquine in vitro. For pvmdr1, pvcrt-o, and pvdhps genes, no resistance-conferring mutations were discovered. However, a highly prevalent (69.2%), single-point mutation (S117N) was found in pvdhfr gene. In addition, tandem repeat polymorphisms existed in pvdhfr and pvdhps genes, which warranted further studies in relation to the parasite resistance to antifolate drugs. The study further suggests that P. vivax populations in central China may still be relatively susceptible to chloroquine and sulfadoxine-pyrimethamine.
    The Korean Journal of Parasitology 12/2012; 50(4):379-84. · 0.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Can we predict the rise and spread of resistance to multi-drug therapy in a more predictable manner? We raise this question after analyzing over 500 Plasmodium vivax isolates collected from different, geographically isolated regions of China for sequence variation in and around the dhfr and dhps genes. We find: that resistance lineages have arisen at least once in each region; that there appears to have been little movement of parasite populations between these areas; and that highly resistant parasites contain dhfr and dhps alleles that are in linkage disequilibrium. We show a direct relationship between this linkage disequilibrium and a parasite's fitness in the absence of drug pressure. Such fitness would increase the spread of drug resistant phenotypes and is thus a selectable trait. These conclusions raise questions about the appropriate use of some other drug combinations to prevent and treat infection.
    Scientific Reports 01/2013; 3:1008. · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The analysis of prevalence and distribution of pvdhfr and pvdhps mutations were performed in 169 samples collected from patients with Plasmodium vivax infection who attended the malaria clinics in the provinces along the three international borders of Thailand (Thai-Myanmar, Thai-Cambodian, and Thai-Malaysian borders). SNP-haplotypes of the pvdhfr at amino acid positions 13, 33, 57, 58, 61, 117, and 173 and of the pvdhps at positions 383 and 553 were examined by nested PCR-RFLP. Significant differences in the prevalence and distribution of pvdhfr and pvdhps combination alleles were observed in P. vivax isolates collected from all the three border areas. The most prevalent combination alleles were triple mutant pvdhfr 57L/58R/117T alleles/double wild-type pvdhps alleles (n=18), double mutant pvdhfr 58R/117N alleles/double wild-type pvdhps alleles (n=10), and triple mutant pvdhfr 58R/61M/117N alleles/double wild-type pvdhps alleles (n=52) or with single mutant pvdhps 383G allele (n=28), respectively. These information on prevalence and patterns of pvdhfr and pvdhps polymorphisms obtained from the present study suggest the presence of SP pressure on P. vivax isolates in Thailand which could be linked to the introduction of malaria from neighboring countries. Results did not support the application of SP for P. vivax control program in Thailand as well as the neighboring countries.
    Acta tropica 07/2013; · 2.79 Impact Factor

Full-text (2 Sources)

Available from
May 27, 2014