• 1

    Ratnapala R, Subramaniam K, Yapabandara MG, Fernando WP, 1984. Chloroquine resistant Plasmodium falciparum in Sri Lanka. Ceylon Med J 29 :135–145.

    • Search Google Scholar
    • Export Citation
  • 2

    Handunnetti SM, Gunewardena DM, Pathirana PP, Ekanayake K, Weerasinghe S, Mendis KN, 1996. Features of recrudescent chloroquine-resistant Plasmodium falciparum infections confer a survival advantage on parasites and have implications for disease control. Trans R Soc Trop Med Hyg 90 :563–567.

    • Search Google Scholar
    • Export Citation
  • 3

    Hapuarachchi HA, Dayanath MY, Abeysundara S, Bandara KB, Abeyewickreme W, de Silva NR, 2004. Chloroquine resistant falciparum malaria among security forces personnel in the northern province of Sri Lanka. Ceylon Med J 49 :47–51.

    • Search Google Scholar
    • Export Citation
  • 4

    Gunasekare D, Perera D, 1996. Multidrug resistant malaria in Sri Lanka. Ceyon Med J 41 :170–171.

  • 5

    Sarukkali C, de Silva S, 1994. Falciparum malaria resistant to sulfadoxine-pyrimethamine and associated with eosinophilia. Ceylon J Child Health 23 :18–20.

    • Search Google Scholar
    • Export Citation
  • 6

    Handunnetti SM, Jayasinghe S, Pathirana PP, Fernando R, Sheriff MH, Mendis KN, 1994. Sulphadoxine-pyrimethamine and chloroquine resistant Plasmodium falciparum infection in Sri Lanka. Ceylon Med J 39 :45–46.

    • Search Google Scholar
    • Export Citation
  • 7

    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.

    • Search Google Scholar
    • Export Citation
  • 8

    Triglia T, Wang P, Sims PF, Hyde JE, Cowman AF, 1998. Allelic exchange at the endogenous genomic locus in Plasmodium falciparum proves the role of dihydropteroate synthase in sulfadoxine-resistant malaria. EMBO J 17 :3807–3815.

    • Search Google Scholar
    • Export Citation
  • 9

    Basco LK, 2003. Molecular epidemiology of malaria in Cameroon. XVI. Longitudinal surveillance of in vitro pyrimethamine resistance in Plasmodium falciparum. Am J Trop Med Hyg 69 :174–178.

    • Search Google Scholar
    • Export Citation
  • 10

    Nzila-Mounda A, Mberu EK, Sibley CH, Plowe CV, Winstanley PA, Watkins WM, 1998. Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain. Antimicrob Agents Chemother 42 :164–169.

    • Search Google Scholar
    • Export Citation
  • 11

    Zolg JW, Plitt JR, Chen G-X, Palmer S, 1989. Point mutations in the dihydrofolate reductase-thymidylate synthase gene as the molecular basis for pyrimethamine resistance in Plasmodium falciparum. Mol Biochem Parasitol 36 :253–262.

    • Search Google Scholar
    • Export Citation
  • 12

    Wang P, Read M, Sims PFG, Hyde JE, 1997. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Mol Microbiol 23 :979–986.

    • Search Google Scholar
    • Export Citation
  • 13

    Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV, 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc Natl Acad Sci USA 94 :1124–1129.

    • Search Google Scholar
    • Export Citation
  • 14

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

  • 15

    Cowman AF, Morry MJ, Biggs BA, Cross GA, Foote SJ, 1988. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 85 :9109–9113.

    • Search Google Scholar
    • Export Citation
  • 16

    Peterson DS, Walliker D, Wellems TE, 1988. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci USA 85 :9114–9118.

    • Search Google Scholar
    • Export Citation
  • 17

    Wang P, Lee CS, Bayoumi R, Djimde A, Doumbo O, Swedberg G, Dao LD, Mshinda H, Tanner M, Watkins WM, Sims PFG, Hyde JE, 1997. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol Biochemi Parasitol 89 :161–177.

    • Search Google Scholar
    • Export Citation
  • 18

    Brooks DR, Wang P, Read M, Watkins WM, Sims PF, Hyde JE, 1994. Sequence variation of the hydroxymethyldihydropterin pyrophosphokinase: dihydropteroate synthase gene in lines of the human malaria parasite, Plasmodium falciparum, with differing resistance to sulfadoxine. Eur J Biochem 224 :397–405.

    • Search Google Scholar
    • Export Citation
  • 19

    Triglia T, Cowman AF, 1994. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 91 :7149–7153.

    • Search Google Scholar
    • Export Citation
  • 20

    Talisuna AO, Nalunkuma-Kazibwe A, Langi P, Mutabingwa TK, Watkins WW, Marck EV, Egwang TG, D’Alessandro U, 2004. Two mutations in dihydrofolate reductase combined with one in the dihydropteroate synthase gene predict sulphadoxine-pyrimethamine parasitological failure in Ugandan children with uncomplicated falciparum malaria. Infect Genet Evol 4 :321–327.

    • Search Google Scholar
    • Export Citation
  • 21

    Talisuna AO, Langi P, Mutabingwa TK, Watkins W, Van Marck E, Egwang TG, D’Alessandro U, 2003. Population-based validation of dihydrofolate reductase gene mutations for the prediction of sulfadoxine-pyrimethamine resistance in Uganda. Trans R Soc Trop Med Hyg 97 :338–342.

    • Search Google Scholar
    • Export Citation
  • 22

    Nzila AM, Mberu EK, Sulo J, Dayo H, Winstanley PA, Sibley CH, Watkins WM, 2000. Towards an Understanding of the mechanism of pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: genotyping of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites. Antimicrob Agents Chemother 44 :991–996.

    • Search Google Scholar
    • Export Citation
  • 23

    Ministry of Health, Sri Lanka. 1999. Annual Health Bulletin.

  • 24

    Ministry of Health, Sri Lanka, 2000. Annual Health Bulletin.

  • 25

    Ministry of Health, Sri Lanka. 2001. Annual Health Bulletin.

  • 26

    Doumbo OK, Kayentao K, Djimde A, Cortese JF, Diourte Y, Konare A, Kublin JG, Plowe CV, 2000. Rapid selection of Plasmodium falciparum dihydrofolate reductase mutants by pyrimethamine prophylaxis. J Infect Dis 182 :993–996.

    • Search Google Scholar
    • Export Citation
  • 27

    Nzila AM, Nduati E, Mberu EK, Sibley CH, Monks SA, Winstanley PA, Watkins WM, 2000. Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate pyrimethamine/sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. J Infect Dis 181 :2023–2028.

    • Search Google Scholar
    • Export Citation
  • 28

    World Health Organization, 2003. Monitoring Antimalarial Drug Resistance: A Report of a Consultation. Geneva: World Health Organization.

  • 29

    Karunaweera N, Carter R, Grau G, Mendis K, 1998. Demonstration of anti-disease immunity to Plasmodium vivax malaria in Sri Lanka using a quantitative method to assess clinical disease. Am J Trop Med Hyg 58 :204–210.

    • Search Google Scholar
    • Export Citation
  • 30

    Duraisingh MT, Curtis J, Warhurst DC, 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. Exp Parasitol 89 :1–8.

    • Search Google Scholar
    • Export Citation
  • 31

    Sibley CH, Brophy VH, Cheesman S, Hamilton KL, Hankins EG, Wooden JM, Kilbey B, 1997. Yeast as a model system to study drugs effective against apicomplexan proteins. Methods 13 :190–207.

    • Search Google Scholar
    • Export Citation
  • 32

    Sikorski RS, Hieter P, 1989. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics 122 :19–27.

    • Search Google Scholar
    • Export Citation
  • 33

    Cortese JF, Plowe CV, 1998. Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutations expressed in yeast. Mol Biochem Parasitol 94 :205–214.

    • Search Google Scholar
    • Export Citation
  • 34

    Huang T, Barclay BJ, Kalman TI, von Borstel RC, Hastings PJ, 1992. The phenotype of a dihydrofolate reductase mutant of Saccharomyces cerevisiae. Gene 121 :167–171.

    • Search Google Scholar
    • Export Citation
  • 35

    Wooden JM, Hartwell LH, Vasquez B, Sibley CH, 1997. Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum. Mol Biochem Parasitol 85 :25–40.

    • Search Google Scholar
    • Export Citation
  • 36

    Ito H, Fukuda Y, Murata K, Kimura A, 1983. Transformation of intact yeast cells treated with alkali cations. J Bacteriol 153 :163–168.

    • Search Google Scholar
    • Export Citation
  • 37

    Desjardins RE, Canfield CJ, Haynes JH, Chulay JD, 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16 :710–718.

    • Search Google Scholar
    • Export Citation
  • 38

    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.

    • Search Google Scholar
    • Export Citation
  • 39

    Jelinek T, Ronn AM, Curtis J, Duraisingh MT, Lemnge MM, Mhina J, Bygbjerg IC, Warhurst DC, 1997. High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium falciparum in isolates from Tanzania without evidence of an association to clinical sulfadoxine/pyrimethamine resistance. Trop Med Int Health 2 :1075–1079.

    • Search Google Scholar
    • Export Citation
  • 40

    Mutabingwa TK, Maxwell CA, Sia IG, Msuya FH, Mkongewa S, Vannithone S, Curtis J, Curtis CF, 2001. A trial of proguanil-dapsone in comparison with sulfadoxine-pyrimethamine for the clearance of Plasmodium falciparum infections in Tanzania. Trans R Soc Trop Med Hyg 95 :433–438.

    • Search Google Scholar
    • Export Citation
  • 41

    Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha F, Chandramohan D, Sharp B, 2003. Antifolate anti-malarial resistance in southeast Africa: a population-based analysis. Lancet 361 :1174–1181.

    • Search Google Scholar
    • Export Citation
  • 42

    EANMAT, 2001. Monitoring antimalarial drug resistance within National Malaria Control Programmes: the EANMAT experience. Trop Med Int Health 6 :891–898.

    • Search Google Scholar
    • Export Citation
  • 43

    Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA, Chimpeni P, Molyneux ME, Taylor TE, 2004. Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. BMJ 328 :545.

    • Search Google Scholar
    • Export Citation
  • 44

    Bates SJ, Winstanley PA, Watkins WM, Alloueche A, Bwika J, Happi TC, Kremsner PG, Kublin JG, Premji Z, Sibley CH, 2004. Rare, highly pyrimethamine-resistant alleles of the Plasmodium falciparum dihydrofolate reductase gene from 5 African sites. J Infect Dis 190 :1783–1792.

    • Search Google Scholar
    • Export Citation
  • 45

    Sibley CH, Hyde JE, Sims PFG, 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.

    • Search Google Scholar
    • Export Citation
  • 46

    Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV, 2002. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 185 :380–388.

    • Search Google Scholar
    • Export Citation
  • 47

    Ahmed A, Bararia D, Vinayak S, Yameen M, Biswas S, Dev V, Kumar A, Ansari MA, Sharma YD, 2004. Plasmodium falciparum isolates in India exhibit a progressive increase in mutations associated with Sulfadoxine-Pyrimethamine resistance. Antimicrob Agents Chemother 48 :879–889.

    • Search Google Scholar
    • Export Citation
  • 48

    Nair S, Williams JT, Brockman A, Paiphun L, Mayxay M, Newton PN, Guthmann JP, Smithuis FM, Hien TT, White NJ, Nosten F, Anderson TJ, 2003. A selective sweep driven by pyrimethamine treatment in Southeast Asian malaria parasites. Mol Biol Evol 20 :1526–1536.

    • Search Google Scholar
    • Export Citation
  • 49

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

    • Search Google Scholar
    • Export Citation
  • 50

    Biswas S, Escalante A, Chaiyaroj S, Angkasekwinai P, Lal AA, 2000. Prevalence of point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes of Plasmodium falciparum isolates from India and Thailand: a molecular epidemiologic study. Trop Med Int Health 5 :737–743.

    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 158 49 10
PDF Downloads 18 10 0
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

POINT MUTATIONS IN THE DIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHASE GENES OF PLASMODIUM FALCIPARUM AND RESISTANCE TO SULFADOXINE-PYRIMETHAMINE IN SRI LANKA

HAPUARACHCHIGE C. HAPUARACHCHIDepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by HAPUARACHCHIGE C. HAPUARACHCHI in
Current site
Google Scholar
PubMed
Close
,
MEEGODA Y. D. DAYANATHDepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by MEEGODA Y. D. DAYANATH in
Current site
Google Scholar
PubMed
Close
,
KANDEYAYE BANDARALAGE A. T. BANDARADepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by KANDEYAYE BANDARALAGE A. T. BANDARA in
Current site
Google Scholar
PubMed
Close
,
SUDUSINGHE ABEYSUNDARADepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by SUDUSINGHE ABEYSUNDARA in
Current site
Google Scholar
PubMed
Close
,
WIMALADHARMA ABEYEWICKREMEDepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by WIMALADHARMA ABEYEWICKREME in
Current site
Google Scholar
PubMed
Close
,
NILANTHI R. DE SILVADepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by NILANTHI R. DE SILVA in
Current site
Google Scholar
PubMed
Close
,
SONIA Y. HUNTDepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by SONIA Y. HUNT in
Current site
Google Scholar
PubMed
Close
, and
CAROL HOPKINS SIBLEYDepartment of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; Department of Genome Sciences, University of Washington, Seattle, Washington

Search for other papers by CAROL HOPKINS SIBLEY in
Current site
Google Scholar
PubMed
Close
Restricted access

Sulfadoxine-pyrimethamine (SP) is the second-line treatment for Plasmodium falciparum malaria in Sri Lanka. Resistance to SP is caused by point mutations in the dihydrofolate reductase (Pf-dhfr) and dihydropteroate synthase (Pf-dhps) genes of P. falciparum. We determined the genotype of Pf-dhfr and Pf-dhps and the clinical response to SP in 30 field isolates of P. falciparum from Sri Lanka. All patients treated with SP had an adequate clinical response. Eighty-five percent (23 of 27) of pure field isolates carried parasites with double mutant alleles of Pf-dhfr (C59R + S108N) and showed about 200-fold higher levels of resistance to pyrimethamine than the wild type in a yeast system. None of the isolates had either known or novel mutations at other positions in the dhfr domain. In contrast, 67% (20 of 30) of the isolates carried parasites that were wild type for Pf-dhps. In Sri Lanka, detection of the triple mutant allele of Pf-dhfr will require tracking mutations at codon 51.

Save