1921
Volume 76, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

We investigated the association between the dihydrofolate reductase () and the dihydropteroate synthase () genotype and sensitivity to the antifolates pyrimethamine, WR99210, chlorcycloguanil, sulfadoxine, and dapsone. Drug responses of 32 isolates were assessed in two systems: schizont maturation inhibition and a yeast expression system. The geometric mean of 50% inhibition concentration (IC) values for pyrimethamine, chlorcycloguanil, WR99210, sulfadoxine, and dapsone were 85 ± 88, 784 ± 662, 95 ± 87, 2,424 ± 2,784, and 1,625 ± 1,801 nM, respectively, for the schizont maturation assay. Five different alleles and four alleles were observed: 26 of 32 quadruple mutant alleles of (F57I,L/S58R/T61M/S117T), four triple mutants (S58R/T61M/S117T, K49C/S58R/S117N), and two double mutant isolates (S58R/S117N). All isolates carried 585V. Twenty four isolates carried double mutant (A383G/A553G), six an additional mutation, S382A,C/A383G/A553G, and two a single mutation, A383G. Increasing geometric mean IC values were observed with increased number of mutations from double to quadruple. Results suggest that quadruple mutant alleles confer decreased sensitivity to pyrimethamine but retain sensitivity to WR99210.

Loading

Article metrics loading...

/content/journals/10.4269/ajtmh.2007.76.1057
2007-06-01
2017-09-26
Loading full text...

Full text loading...

/deliver/fulltext/14761645/76/6/0761057.html?itemId=/content/journals/10.4269/ajtmh.2007.76.1057&mimeType=html&fmt=ahah

References

  1. Mendis K, Sina BJ, Marchesini P, Carter R, 2001. The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg 64 (Suppl 1–2) : 97–106.
  2. 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.
  3. Singh N, Chand SK, Mishra AK, Bharti PK, Singh MP, Ahluwalia TP, Dash AP, 2006. Epidemiology of malaria in an area of low transmission in central India. Am J Trop Med Hyg 75 : 812–816.
  4. World Health Organization, 2001. The Use of Antimalarial Drugs. Report of a WHO Informal Consultation. Geneva: World Health Organization.
  5. Basco LK, Eldin de Pecoulas P, Wilson CM, Le Bras J, Mazabraud A, 1995. Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum. Mol Biochem Parasitol 69 : 135–138.
  6. 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 U S A 85 : 9109–9113.
  7. Hyde JE, 2005. Drug-resistant malaria. Trends Parasitol 21 : 494–498.
  8. 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 U S A 85 : 9114–9118.
  9. 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 U S A 94 : 13944–13949.
  10. Wu Y, Kirkman LA, Wellems TE, 1995. Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine. Proc Natl Acad Sci U S A 90 : 1130–1134.
  11. Crabb BS, 2002. Transfection technology and the study of drug resistance in the malaria parasite. Drug Resist Updat 5 : 126–130.
  12. Gregson A, Plowe CV, 2005. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57 : 117–145.
  13. Eldin de Pecoulas P, Basco LK, Tahar R, Ouatas T, Mazabraud A, 1998. Analysis of the Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene sequence. Gene 211 : 177–185.
  14. Russell BM, Udomsangpetch R, Rieckmann KH, Kotecka BM, Coleman RE, Sattabongkot J, 2003. Simple in vitro assay for determining the sensitivity of Plasmodium vivax isolates from fresh human blood to antimalarials in areas where P. vivax is endemic. Antimicrob Agents Chemother 47 : 170–173.
  15. Chotivanich K, Udomsangpetch R, Chierakul W, Newton PN, Ruangveerayuth R, Pukrittayakamee S, Looareesuwan S, White NJ, 2004. In vitro efficacy of antimalarial drugs against Plasmodium vivax on the western border of Thailand. Am J Trop Med Hyg 70 : 395–397.
  16. Kosaisavee V, Suwanarusk R, Nosten F, Kyle DE, Barrends M, Jones J, Price R, Russell B, Lek-Uthai U, 2006. Plasmodium vivax: isotopic, PicoGreen, and microscopic assays for measuring chloroquine sensitivity in fresh and cryopreserved isolates. Exp Parasitol 114 : 34–39.
  17. Kocken C, van der Wel A, Arbe-Barnes S, Brun R, Matile H, Scheurer C, Wittlin S, Thomas A, 2006. Plasmodium vivax: in vitro susceptibility of blood stages to synthetic trioxolane compounds and the diamidine DB75. Exp Parasitol 113 : 197–200.
  18. 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.
  19. 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.
  20. Hastings MD, Sibley CH, 2002. Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax. Proc Natl Acad Sci U S A 99 : 13137–13141.
  21. 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.
  22. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR, 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2 : 209–218.
  23. Wongsrichanalai C, Sirichaisinthop J, Karwacki JJ, Congpuong K, Miller RS, Pang L, Thimasarn K, 2001. Drug resistant malaria on the Thai-Myanmar and Thai-Cambodian borders. Southeast Asian J Trop Med Public Health 32 : 41–49.
  24. Bruce MC, Galinski MR, Barnwell JW, Snounou G, Day KP, 1999. Polymorphism at the merozoite surface protein-3alpha locus of Plasmodium vivax: global and local diversity. Am J Trop Med Hyg 61 : 518–525.
  25. Cui L, Escalante AA, Imwong M, Snounou G, 2003. The genetic diversity of Plasmodium vivax populations. Trends Parasitol 19 : 220–226.
  26. 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.
  27. 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.
  28. 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.
  29. Gietz RD, Woods RA, 2002. Transformation of yeast by lithium acetate/single-stranded carrier DNA/polyethylene glycol method. Methods Enzymol 350 : 87–96.
  30. Mberu EK, Nzila AM, Nduati E, Ross A, Monks SM, Kokwaro GO, Watkins WM, Hopkins Sibley C, 2002. Plasmodium falciparum: in vitro activity of sulfadoxine and dapsone in field isolates from Kenya: point mutations in dihydropteroate synthase may not be the only determinants in sulfa resistance. Exp Parasitol 101 : 90–96.
  31. Hyde JE, 2002. Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs. Microbes Infect 4 : 165–174.
  32. 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.
  33. 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.
  34. 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.
  35. Valecha N, Joshi H, Eapen A, Ravinderan J, Kumar A, Prajapati SK, Ringwald P, 2006. Therapeutic efficacy of chloroquine in Plasmodium vivax from areas with different epidemiological patterns in India and their Pvdhfr gene mutation pattern. Trans R Soc Trop Med Hyg 100 : 831–837.
  36. Menegon M, Majori G, Severini C, 2006. Genetic variations of the Plasmodium vivax dihydropteroate synthase gene. Acta Trop 98 : 196–199.
  37. 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.
  38. Mberu EK, Mosobo MK, Nzila AM, Kokwaro GO, Sibley CH, Watkins WM, 2000. The changing in vitro susceptibility pattern to pyrimethamine/sulfadoxine in Plasmodium falciparum field isolates from Kilifi, Kenya. Am J Trop Med Hyg 62 : 396–401.
  39. 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.
  40. Watkins WM, Sixsmith DG, Chulay JD, Spencer HC, 1985. Antagonism of sulfadoxine and pyrimethamine antimalarial activity in vitro by p-aminobenzoic acid, p-aminobenzoylglutamic acid and folic acid. Mol Biochem Parasitol 14 : 55–61.
  41. Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, Hills E, Watkins W, 2001. Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania. Lancet 358 : 1218–1223.
  42. Hastings MD, Bates SJ, Blackstone EA, Monks SM, Mutabingwa TK, Sibley CH, 2002. Highly pyrimethamine-resistant alleles of dihydrofolate reductase in isolates of Plasmodium falciparum from Tanzania. Trans R Soc Trop Med Hyg 96 : 674–676.
  43. 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.
  44. Snounou G, White NJ, 2004. The co-existence of Plasmodium: sidelights from falciparum and vivax malaria in Thailand. Trends Parasitol 20 : 333–339.
  45. Mayxay M, Pukrittayakamee S, Newton PN, White NJ, 2004. Mixed-species malaria infections in humans. Trends Parasitol 20 : 233–240.
  46. 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.
  47. Thimasarn K, 1999. Malaria Control Program in Thailand. Malikul S, ed. Bangkok, Thailand: Malaria Division, Department of Communicable Disease Control, Ministry of Public Health, Thailand, 88–102.
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.2007.76.1057
Loading
/content/journals/10.4269/ajtmh.2007.76.1057
Loading

Data & Media loading...

  • Received : 06 Dec 2006
  • Accepted : 11 Feb 2007

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error