Geographical Distribution of Amino Acid Mutations in Plasmodium vivax DHFR and DHPS from Malaria Endemic Areas of Thailand

Kanchana Rungsihirunrat Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand; Department of Parasitology, Phramongkutklao College of Medicine, Thailand; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by Kanchana Rungsihirunrat in
Current site
Google Scholar
PubMed
Close
,
Carol Hopkins Sibley Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand; Department of Parasitology, Phramongkutklao College of Medicine, Thailand; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by Carol Hopkins Sibley in
Current site
Google Scholar
PubMed
Close
,
Mathirut Mungthin Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand; Department of Parasitology, Phramongkutklao College of Medicine, Thailand; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by Mathirut Mungthin in
Current site
Google Scholar
PubMed
Close
, and
Kesara Na-Bangchang Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand; Department of Parasitology, Phramongkutklao College of Medicine, Thailand; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by Kesara Na-Bangchang in
Current site
Google Scholar
PubMed
Close
Restricted access

Both malaria treatment and prophylaxis target the parasite dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) enzymes. Specific point mutations in these genes confer resistance to sulfadoxine-pyrimethamine (SP) in both Plasmodium falciparum and P. vivax. We used direct sequencing to examine the prevalence of point mutations in pvdhps and pvdhfr in 160 P. vivax isolates collected from areas along the international borders of Thailand. Results show that the majority of the isolates harbored a quadruple mutant allele of pvdhfr and a double mutant allele of pvdhps, but the distribution was not uniform. The highly mutant allele combination was especially prevalent along the Thai-Myanmar border, whereas the majority of the isolates from areas along the Thai-Cambodian and Thai-Malaysian borders carried double mutant alleles of pvdhfr and single mutant alleles of pvdhps. Novel mutations that have not been identified previously at codon 512 of pvdhps (K512M, K512E, K512T) were also found.

Author Notes

  • 1

    Malaria Control Program in Thailand. Ministry of Public Health. 2003.

  • 2

    Chareonviriyaphap T, Bangs MJ, Ratanatham S, 2000. Status of malaria in Thailand. Southeast Asian J Trop Med Public Health 31 :225–237.

  • 3

    Zhou G, Sirichaisinthop J, Sattabongkot J, Jones J, Bjornstad ON, Yan G, Cui L, 2005. Spatio-temporal distribution of Plasmodium falciparum and P. vivax malaria in Thailand. Am J Trop Med Hyg 72 :256–262.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Sornmani S, Butraporn P, Fungladda W, Okanurak K, Dissapongsa S, 1983. Migration and disease problems: a study of pattern of migration in an endemic area of malaria in Thailand. Southeast Asian J Trop Med Public Health 14 :64–68.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Pinichpongse S, Doberstyn EB, Cullen JR, Yisunsri L, Thongsombun Y, Thimasarn K, 1982. An evaluation of five regimens for the outpatient therapy of falciparum malaria in Thailand 1980–81. Bull World Health Organ 60 :907–912.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Thaithong S, Chan SW, Songsomboon S, Wilairat P, Seesod N, Sueblinwong T, Goman M, Ridley R, Beale G, 1992. Pyrimethamine resistant mutations in Plasmodium falciparum. Mol Biochem Parasitol 52 :149–157.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Gregson A, Plowe CV, 2005. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57 :117–145.

  • 8

    Snounou G, White NJ, 2004. The co-existence of Plasmodium: sidelights from falciparum and vivax malaria in Thailand. Trends Parasitol 20 :333–339.

  • 9

    Imwong M, Pukrittayakamee S, Renia L, Letourneur F, Charlieu JP, Leartsakulpanich U, Looareesuwan S, White NJ, Snounou G, 2003. Novel point mutations in the dihydrofolate reductase gene of Plasmodium vivax: evidence for sequential selection by drug pressure. Antimicrob Agents Chemother 47 :1514–1521.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Baird JK, 2004. Chloroquine resistance in Plasmodium vivax. Antimicrob Agents Chemother 48 :4075–4083.

  • 11

    Sattabongkot J, Tsuboi T, Zollner GE, Sirichaisinthop J, Cui L, 2004. Plasmodium vivax transmission: chances for control? Trends Parasitol 20 :192–198.

  • 12

    Foote SJ, Cowman AF, 1994. The mode of action and the mechanism of resistance to antimalarial drugs. Acta Trop 56 :157–171.

  • 13

    Imwong M, Pukrittakayamee S, Looareesuwan S, Pasvol G, Poirreiz J, White NJ, Snounou G, 2001. Association of genetic mutations in Plasmodium vivax dhfr with resistance to sulfadoxine-pyrimethamine: geographical and clinical correlates. Antimicrob Agents Chemother 45 :3122–3127.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Triglia T, Menting JG, Wilson C, Cowman AF, 1997. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 94 :13944–13949.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, Winstanley PA, Estrada-Franco JG, Mollinedo RE, Avila JC, Cespedes JL, Carter D, Doumbo OK, 1997. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J Infect Dis 176 :1590–1596.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Hawkins VN, Joshi H, Rungsihirunrat K, Na-Bangchang K, Sibley CH, 2007. Antifolates can have a role in the treatment of Plasmodium vivax. Trends Parasitol 23 :213–222.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Young MD, Burgess RW, 1959. Pyrimethamine resistance in Plasmodium vivax malaria. Bull World Health Organ 20 :27–36.

  • 18

    Hastings MD, Porter KM, Maguire JD, Susanti I, Kania W, Bangs MJ, Sibley CH, Baird JK, 2004. Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine. J Infect Dis 189 :744–750.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Leslie T, Mayan MI, Hasan MA, Safi MH, Klinkenberg E, Whitty CJ, Rowland M, 2007. Sulfadoxine-pyrimethamine, chlorproguanil-dapsone, or chloroquine for the treatment of Plasmodium vivax malaria in Afghanistan and Pakistan: a randomized controlled trial. JAMA 297 :2201–2209.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Hastings MD, Sibley CH, 2002. Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax. Proc Natl Acad Sci USA 99 :13137–13141.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Konchom S, Singhasivanon P, Kaewkungwal J, Chupraphawan S, Thimasarn K, Kidson C, Rojanawatsirivet C, Yimsamran S, Looareesuwan S, 2003. Trend of malaria incidence in highly endemic provinces along the Thai borders, 1991–2001. Southeast Asian J Trop Med Public Health 34 :486–494.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Congpuong K, Na-Bangchang K, Thimasarn K, Tasanor U, Wernsdorfer WH, 2002. Sensitivity of Plasmodium vivax to chloroquine in Sa Kaeo Province, Thailand. Acta Trop 83 :117–121.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Mayxay M, Pukritrayakamee S, Chotivanich K, Imwong M, Looareesuwan S, White NJ, 2001. Identification of cryptic coinfection with Plasmodium falciparum in patients presenting with vivax malaria. Am J Trop Med Hyg 65 :588–592.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Mayxay M, Pukrittayakamee S, Newton PN, White NJ, 2004. Mixed-species malaria infections in humans. Trends Parasitol 20 :233–240.

  • 25

    Hyde JE, 2005. Drug-resistant malaria. Trends Parasitol 21 :494–498.

  • 26

    de Pecoulas PE, Tahar R, Ouatas T, Mazabraud A, Basco LK, 1998. Sequence variations in the Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene and their relationship with pyrimethamine resistance. Mol Biochem Parasitol 92 :265–273.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Tjitra E, Baker J, Suprianto S, Cheng Q, Anstey NM, 2002. Therapeutic efficacies of artesunate-sulfadoxine-pyrimethamine and chloroquine-sulfadoxine-pyrimethamine in vivax malaria pilot studies: relationship to Plasmodium vivax dhfr mutations. Antimicrob Agents Chemother 46 :3947–3953.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Kaur S, Prajapati SK, Kalyanaraman K, Mohmmed A, Joshi H, Chauhan VS, 2006. Plasmodium vivax dihydrofolate reductase point mutations from the Indian subcontinent. Acta Trop 97 :174–180.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    de Pecoulas PE, Tahar R, Yi P, Thai KH, Basco LK, 2004. Genetic variation of the dihydrofolate reductase gene in Plasmodium vivax in Snoul, northeastern Cambodia. Acta Trop 92 :1–6.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Na BK, Lee HW, Moon SU, In TS, Lin K, Maung M, Chung GT, Lee JK, Kim TS, Kong Y, 2005. Genetic variations of the dihydrofolate reductase gene of Plasmodium vivax in Mandalay Division, Myanmar. Parasitol Res 96 :321–325.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Prajapati SK, Joshi H, Valecha N, Reetha AM, Eapen A, Kumar A, Das MK, Yadav RS, Rizvi MA, Dash AP, 2007. Allelic polymorphism in the Plasmodium vivax dihydrofolate reductase gene among Indian field isolates. Clin Microbiol Infect 13 :331–334.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, Magill AJ, Su XZ, 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418 :320–323.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T, 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305 :1124.

  • 34

    Imwong M, Pukrittayakamee S, Cheng Q, Moore C, Looareesuwan S, Snounou G, White NJ, Day NP, 2005. Limited polymorphism in the dihydropteroate synthetase gene (dhps) of Plasmodium vivax isolates from Thailand. Antimicrob Agents Chemother 49 :4393–4395.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Leartsakulpanich U, Imwong M, Pukrittayakamee S, White NJ, Snounou G, Sirawaraporn W, Yuthavong Y, 2002. Molecular characterization of dihydrofolate reductase in relation to antifolate resistance in Plasmodium vivax. Mol Biochem Parasitol 119 :63–73.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Tahar R, de Pecoulas PE, Basco LK, Chiadmi M, Mazabraud A, 2001. Kinetic properties of dihydrofolate reductase from wild-type and mutant Plasmodium vivax expressed in Escherichia coli. Mol Biochem Parasitol 113 :241–249.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Hastings MD, Maguire JD, Bangs MJ, Zimmerman PA, Reeder JC, Baird JK, Sibley CH, 2005. Novel Plasmodium vivax dhfr alleles from the Indonesian Archipelago and Papua New Guinea: association with pyrimethamine resistance determined by a Saccharomyces cerevisiae expression system. Antimicrob Agents Chemother 49 :733–740.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Rungsihirunrat K, Na-Bangchang K, Hawkins VN, Mungthin M, Sibley CH, 2007. Sensitivity to antifolates and genetic analysis of Plasmodium vivax isolates from Thailand. Am J Trop Med Hyg 76 :1057–1065.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Martin DC, Arnold JD, 1969. Trimethroprim and sulfalene therapy of Plasmodium vivax. J Clin Pharmacol J New Drugs 9 :155–159.

  • 40

    Rieckmann KH, McNamara JV, Frischer H, Stockert TA, Carson PE, Powell RD, 1968. Effects of chloroquine, quinine, and cycloguanil upon the maturation of asexual erythrocytic forms of two strains of Plasmodium falciparum in vitro. Am J Trop Med Hyg 17 :661–671.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Korsinczky M, Fischer K, Chen N, Baker J, Rieckmann K, Cheng Q, 2004. Sulfadoxine resistance in Plasmodium vivax is associated with a specific amino acid in dihydropteroate synthase at the putative sulfadoxine-binding site. Antimicrob Agents Chemother 48 :2214–2222.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Sibley CH, Hyde JE, Sims PF, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM, 2001. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol 17 :582–588.

    • PubMed
    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 53 53 5
Full Text Views 320 5 0
PDF Downloads 91 2 0
 
Membership Banner
 
 
 
Affiliate Membership Banner
 
 
Research for Health Information Banner
 
 
CLOCKSS
 
 
 
Society Publishers Coalition Banner
Save