Article

Mutations in the Antifolate-Resistance-Associated Genes Dihydrofolate Reductase and Dihydropteroate Synthase in Plasmodium vivax Isolates from Malaria-Endemic Countries

Gachon University, 성남시, Gyeonggi-do, South Korea
The American journal of tropical medicine and hygiene (Impact Factor: 2.7). 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.

Download full-text

Full-text

Available from: Jetsumon Sattabongkot
  • Source
    • "The common Pvdhfr alleles 58R and 117T/N were found in the southeast Asian countries of East Timor (de Almeida et al. 2010), Thailand (Imwong et al. 2001, Lu et al. 2010), Myanmar (Lu et al. 2010), Vietnam and the Philippines (Auliff et al. 2006), in India (Kaur et al. 2006, Alam et al. 2007), in the African countries of French Guinea (Barnadas et al. 2009) and Madagascar (Barnadas et al. 2008). Mutants in Pvdhps at amino acids 383 and 553 were found at low prevalence in most geographic regions including East Timor (de Almeida et al. 2010), Korea (Lu et al. 2010), Iran (Zakeri et al. 2009) and Pakistan (Zakeri et al. 2011), whereas they were found at high prevalence in Thailand (Imwong et al. 2005, Rungsihirunrat et al. 2008). Isolates carrying Pvdhps double mutations coexisting with multiple mutations (4 or more amino acids) of Pvdhfr are being reported with increasing frequency (Imwong et al. 2005). "

    Full-text · Article · Jan 2014 · Memórias do Instituto Oswaldo Cruz
  • Source
    • "Antifolates interfere with folate metabolism, essential for parasite survival, via inhibition of the enzymes dihydrofolate reductase [152] and dihydropteroate synthase [153]. Both humans and parasites can convert folic acid to tretrahydrofolic acid, which has a key role in the biosynthesis of thymine, purine nucleotides and several amino acids. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells. Different types of encapsulating structure, targeting molecule, and antimalarial compound will be discussed for the assembly of Trojan horse nanocapsules capable of targeting with complete specificity diseased cells and of delivering inside them their antimalarial cargo with the objective of eliminating the parasite with a single dose. Nanotechnology can also be applied to the discovery of new antimalarials through single-molecule manipulation approaches for the identification of novel drugs targeting essential molecular components of the parasite. Finally, methods for the diagnosis of malaria can benefit from nanotools applied to the design of microfluidic-based devices for the accurate identification of the parasite's strain, its precise infective load, and the relative content of the different stages of its life cycle, whose knowledge is essential for the administration of adequate therapies. The benefits and drawbacks of these nanosystems will be considered in different possible scenarios, including cost-related issues that might be hampering the development of nanotechnology-based medicines against malaria with the dubious argument that they are too expensive to be used in developing areas.
    Full-text · Article · Oct 2013 · Current Medicinal Chemistry
  • Source
    • "The common Pvdhfr alleles 58R and 117T/N were found in the southeast Asian countries of East Timor (de Almeida et al. 2010), Thailand (Imwong et al. 2001, Lu et al. 2010), Myanmar (Lu et al. 2010), Vietnam and the Philippines (Auliff et al. 2006), in India (Kaur et al. 2006, Alam et al. 2007), in the African countries of French Guinea (Barnadas et al. 2009) and Madagascar (Barnadas et al. 2008). Mutants in Pvdhps at amino acids 383 and 553 were found at low prevalence in most geographic regions including East Timor (de Almeida et al. 2010), Korea (Lu et al. 2010), Iran (Zakeri et al. 2009) and Pakistan (Zakeri et al. 2011), whereas they were found at high prevalence in Thailand (Imwong et al. 2005, Rungsihirunrat et al. 2008). Isolates carrying Pvdhps double mutations coexisting with multiple mutations (4 or more amino acids) of Pvdhfr are being reported with increasing frequency (Imwong et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Malaria is the most important public health problem in several countries. In Thailand, co-infections of Plasmodium vivax and Plasmodium falciparum are common. We examined the prevalence and patterns of mutations in P. vivax dihydrofolate reductase (Pvdhfr) and P. vivax dihydropteroate synthase (Pvdhps) in 103 blood samples collected from patients with P. vivax infection who had attended the malaria clinic in Mae Sot, Tak Province during 2009 and 2010. Using nested polymerase chain reaction-restriction fragment length polymorfism, we examined single nucleotide polymorphisms-haplotypes at amino acid positions 13, 33, 57, 58, 61, 117 and 173 of Pvdhfr and 383 and 553 of Pvdhps. All parasite isolates carried mutant Pvdhfr alleles, of which the most common alleles were triple mutants (99%). Eight different types of Pvdhfr and combination alleles were found, as follows: 57I/58R/117T, 57I/58R/117T, 57I/58R/117T/N, 57L/58R/117T, 57L/58R/117T, 58R/61M/117N, 58R/61M/117N and 13L/57L/58R/117T. The most common Pvdhfr alleles were 57I/58R/117T (77.7%), 57I/58R/117T/N (1%), 57L/58R/117T (5.8%) and 58R/61M/117N (14.5%). The most common Pvdhfr alleles were 57I/58R/117T (77.7%), 57I/58R/117T/N (1%), 57L/58R/117T (5.8%) and 58R/61M/117N (14.5%). Additionally, we recovered one isolate of a carrying a quadruple mutant allele, 13L/57L/58R/117T. The most prevalent Pvdhps allele was a single mutation in amino acid 383 (82.5%), followed by the wild-type A383/A553 (17.5%) allele. Results suggest that all P. vivax isolates in Thailand carry some combination of mutations in Pvdhfr and Pvdhps. Our findings demonstrate that development of new antifolate drugs effective against sulfadoxine-pyrimethamine-resistant P. vivax is required.
    Preview · Article · Aug 2011 · Memórias do Instituto Oswaldo Cruz
Show more