1887

Chapter 23 : Mechanisms of Antimalarial Drug Action and Resistance

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Mechanisms of Antimalarial Drug Action and Resistance, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817558/9781555813307_Chap23-1.gif /docserver/preview/fulltext/10.1128/9781555817558/9781555813307_Chap23-2.gif

Abstract:

This chapter talks about the modes of action and mechanisms of resistance to the antifolate drugs sulfadoxine-pyrimethamine (SP), pyrimethamine, and cycloguanil, as well as the quinoline-based drugs, notably chloroquine (CQ), mefloquine (MFQ), and quinine (QN). Antifolates comprise a group of drugs that work through inhibition of folate metabolism of various organisms, including malaria parasites. In all species, as well as other protozoa and some plants, dihydrofolate reductase (DHFR) exists as a bifunctional enzyme that includes thymidylate synthase (TS), which forms deoxythymidylate (dTMP) from deoxyuridylate, while another substrate, methylenetetrahydrofolate, is converted to dihydrofolate (DHF). Resistance to DHFR inhibitors, including pyrimethamine and cycloguanil, arose soon after their deployment as antimalarials. As an alternative to SP, a combination of dapsone with chlorcycloguanil, administered as its prodrug chlorproguanil, has recently been developed. Chloroquine use began worldwide in the late 1940s, and for several decades, this drug remained the gold standard in the prevention and treatment of uncomplicated malaria. Mechanistic models relating pH-dependent physiological changes in relation to CQ resistance (CQR) have recently seen intriguing yet contradictory developments. Direct evidence in support of a determining role for in CQR first came from transfection studies showing that coexpression of mutant in CQ-sensitive (CQS) parasites produced low-level, VP-reversible CQR. Focused and applied efforts from the academic, industrial, funding, and health care sectors on a significantly greater scale are vital to achieving any success in reducing the devastating impact that malaria maintains on the poorest nations of this world.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

(A) Chemical reaction catalyzed by dihydrofolate reductase and structures of selected antimalarial DHFR inhibitors. The prodrug proguanil is converted into the DHFR inhibitor cycloguanil. (B) Chemical reaction catalyzed by dihydropteroate synthase, together with the structures of the DHPS inhibitors sulfadoxine and dapsone.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

De novo synthesis, salvage, and utilization of folate cofactors in malaria parasites. Most enzymes in the de novo synthesis pathway in the genome have been identified, with the exception of dihydroneopterin aldolase. The salvage pathways have been investigated mainly through metabolic labeling analyses.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Possible evolution of antifolate resistance through cumulative mutations. The first mutation is considered to be S108N, followed by other mutations that confer increasing levels of resistance. The quadruple mutant N51I+C59R+S108N+I164L, resistant to both pyrimethamine and cycloguanil, is found in southeast Asia, while C50R+N51I+S108N+I164L might be present at very low levels in Africa. Another mutant, A16V+S108T, is resistant only to cycloguanil and not pyrimethamine.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

Chemical structures of major antimalarial quionolines, as well as the endoperoxide-containing drug artemisinin.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5
FIGURE 5

PfCRT predicted structure. PfCRT has been postulated to possess 10 transmembrane helices, with the N and C termini extending into the parasite cytoplasm. Filled circles indicate the positions of mutations published from full-length cDNA sequences identified in CQ-resistant parasites from field samples, as well as additional mutations identified in amantadine- and halofantrine-resistant parasites selected in vitro ( Table 1 ). (Reprinted from [ ] with permission from the publisher.)

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6a
FIGURE 6a

Cumulative percentage of patients free from malaria after treatment with MFQ monotherapy (A) or MFQ and 3 days of artesunate (B). Open circles, 1 copy; triangles, 2 copies; diamonds, 3+ copies. (Reprinted from The Lancet [ ] with permission from the publisher.)

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6b
FIGURE 6b

Cumulative percentage of patients free from malaria after treatment with MFQ monotherapy (A) or MFQ and 3 days of artesunate (B). Open circles, 1 copy; triangles, 2 copies; diamonds, 3+ copies. (Reprinted from The Lancet [ ] with permission from the publisher.)

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817558.chap23
1. Aikawa, M. 1972. High-resolution autoradiography of malarial parasites treated with 3H-chloroquine. Am. J. Pathol. 67:277284.
2. Ariey, F.,, J. B. Duchemin,, and V. Robert. 2003. Metapopulation concepts applied to falciparum malaria and their impacts on the emergence and spread of chloroquine resistance. Infect. Genet. Evol. 2:185192.
3. Atreya, C. E.,, and K. S. Anderson. 2004. Kinetic characterization of bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis: a paradigm shift for ts activity and channeling behavior. J. Biol. Chem. 279:1831418322.
4. Babiker, H. A.,, S. J. Pringle,, A. Abdel-Muhsin,, M. Mackinnon,, P. Hunt,, and D. Walliker. 2001. High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance gene pfmdr1. J. Infect. Dis. 183:15351538.
5. Baird, J. K. 2004. Chloroquine resistance in Plasmodium vivax. Antimicrob.Agents Chemother. 48:40754083.
6. Barnes, D. A.,, S. J. Foote,, D. Galatis,, D. J. Kemp,, and A. F. Cowman. 1992. Selection for high-level chloroquine resistance results in deamplification of the pfmdr 1 gene and increased sensitivity to mefloquine in Plasmodium falciparum. EMBO J. 11:30673075.
7. Basco, L. K.,, and P. Ringwald. 2002. Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives. Am. J.Trop. Med. Hyg. 66:667671.
8. Bennett, T. N.,, A. D. Kosar,, L. M. Ursos,, S. Dzekunov,, A. B. S. Sidhu,, D.A. Fidock,, and P. D. Roepe. 2004. Drug resistance-associated pfCRT mutations confer decreased Plasmodium falciparum digestive vacuolar pH. Mol.Biochem. Parasitol. 133:99114.
9. Berglez, J.,, P. Iliades,, W. Sirawaraporn,, P. Coloe,, and I. Macreadie. 2004. Analysis in Escherichia coli of Plasmodium falciparum dihydropteroate synthase (DHPS) alleles implicated in resistance to sulfadoxine. Int. J. Parasitol. 34:95100.
10. Brasseur, P.,, J. Kouamouo,, R. Moyou-Somo,, and P. Druilhe. 1992. Multi-drug resistant falciparum malaria in Cameroon in 1987-1988.I.Stable figures of prevalence of chloroquine- and quinine-resistant isolates in the original foci. Am. J.Trop. Med. Hyg. 46:17.
11. Bray, P. G.,, R. E. Howells,, and S. A. Ward. 1992. Vacuolar acidification and chloroquine sensitivity in Plasmodium falciparum. Biochem. Pharmacol. 43:12191227.
12. Bray, P. G.,, S. R. Hawley,, M. Mungthin,, and S. A. Ward. 1996a. Physicochemical properties correlated with drug resistance and the reversal of drug resistance in Plasmodium falciparum. Mol. Pharmacol. 50:15591566.
13. Bray, P. G.,, S. R. Hawley,, and S. A. Ward. 1996b. 4-Aminoquinoline resistance of Plasmodium falciparum: insights from the study of amodiaquine uptake. Mol. Pharmacol. 50:15511558.
14. Bray, P. G.,, M. Mungthin,, R. G. Ridley,, and S. A. Ward. 1998. Access to hematin: the basis of chloroquine resistance. Mol. Pharmacol. 54:170179.
15. Bray, P. G.,, K. J. Saliba,, J. D. Davies,, D. G. Spiller,, M. R. White,, K. Kirk,, and S. A. Ward. 2002. Distribution of acridine orange fluorescence in Plasmodium falciparum-infected erythrocytes and its implications for the evaluation of digestive vacuole pH. Mol. Biochem. Parasitol. 119:301304.
16. Bray, P. G.,, R. E. Martin,, L. Tilley,, S. A. Ward,, K. Kirk,, and D. A. Fidock. 2005. Defining the role of PfCRT in P. falciparum chloroquine resistance. Mol. Microbiol. 56:323333.
17. Brooks, D. R.,, P. Wang,, M. Read,, W. M. Watkins,, P. F. Sims,, and J. E. Hyde. 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. 224:397405.
18. Bruce-Chwatt, L. J. (ed.). 1981. Chemotherapy of Malaria, 2nd ed. World Health Organisation,Geneva, Switzerland.
19. Canfield, C. J.,, W. K. Milhous,, A. L. Ager,, R. N. Rossan,, T. R. Sweeney,, N. J. Lewis,, and D. P. Jacobus. 1993. PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists. Am. J.Trop. Med. Hyg. 49:121126.
20. Chaiyaroj, S. C.,, A. Buranakiti,, P. Angkasekwinai,, S. Looressuwan,, and A. F. Cowman. 1999. Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug-resistant Plasmodium falciparum isolates from Thailand. Am.J.Trop.Med. Hyg. 61:780783.
21. Chen, N.,, B. Russell,, J. Staley,, B. Kotecka,, P. Nasveld,, and Q. Cheng. 2001. Sequence polymorphisms in pfcrt are strongly associated with chloroquine resistance in Plasmodium falciparum. J. Infect. Dis. 183:15431545.
22. Chen, N.,, D. E. Kyle,, C. Pasay,, E. V. Fowler,, J. Baker,, J. M. Peters,, and Q. Cheng. 2003. pfcrt allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum isolates from the Philippines. Antimicrob. Agents Chemother. 47:35003505.
23. Chen, N.,, D. W. Wilson,, C. Pasay,, D. Bell,, L. B. Martin,, D. Kyle,, and Q. Cheng. 2005. Origin and dissemination of chloroquine-resistant Plasmodium falciparum with mutant pfcrt alleles in the Philippines. Antimicrob. Agents Chemother. 49:21022105.
24. Chevli, R.,, and C. D. Fitch. 1982. The antimalarial drug mefloquine binds to membrane phospholipids. Antimicrob. Agents Chemother. 21:581586.
25. Chou, A. C.,, R. Chevli,, and C.D. Fitch. 1980. Ferriprotoporphyrin IX fulfills the criteria for identification as the chloroquine receptor of malaria parasites. Biochemistry 19:15431549.
26. Chou, A. C.,, and C.D. Fitch. 1993. Control of heme polymerase by chloroquine and other quinoline derivatives. Biochem. Biophys. Res. Commun. 195:422427.
27. Chusacultanachai, S.,, P. Thiensathit,, B. Tarnchompoo,, W. Sirawaraporn,, and Y. Yuthavong. 2002. Novel antifolate resistant mutations of Plasmodium falciparum dihydrofolate reductase selected in Escherichia coli. Mol. Biochem. Parasitol. 120:6172.
28. Cooper, R. A.,, M.T. Ferdig,, X. Z. Su,, L. M. Ursos,, J. Mu,, T. Nomura,, H. Fujioka,, D.A. Fidock,, P. D. Roepe,, and T. E. Wellems. 2002. Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum. Mol. Pharmacol. 61:3542.
29. Cowman, A. F.,, M. J. Morry,, B. A. Biggs,, G. A. Cross,, and S. J. Foote. 1988. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 85:91099113.
30. Cowman, A. F.,, S. Karcz,, D. Galatis,, and J. G. Culvenor. 1991. A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. J. Cell Biol. 113:10331042.
31. Cowman, A. F.,, D. Galatis,, and J. K. Thompson. 1994. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc. Natl. Acad. Sci. USA 91:11431147.
32. Cowman, A. F., 1998. The molecular basis of resistance to the sulfones, sulfonamides and dihydrofolate reductase inhibitors, p. 317330. In I.W. Sherman (ed.), Malaria: Parasite Biology, Pathogenesis and Protection.ASM Press,Washington, D.C.
33. Djimdé, A.,, O. K. Doumbo,, J. F. Cortese,, K. Kayentao,, S. Doumbo,, Y. Diourte,, A. Dicko,, X. Z. Su,, T. Nomura,, D. A. Fidock,, T. E. Wellems,, and C. V. Plowe. 2001a. A molecular marker for chloroquine-resistant falciparum malaria. N. Engl. J. Med. 344:257263.
34. Djimdé, A.,, O. K. Doumbo,, R. W. Steketee,, and C. V. Plowe. 2001b. Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria. Lancet 358:890891.
35. Djimdé, A. A.,, O. K. Doumbo,, O. Traore,, A. B. Guindo,, K. Kayentao,, Y. Diourte,, S. Niare-Doumbo,, D. Coulibaly,, A. K. Kone,, Y. Cissoko,, M. Tekete,, B. Fofana,, A. Dicko,, D. A. Diallo,, T. E. Wellems,, D. Kwiatkowski,, and C.V. Plowe. 2003. Clearance of drug-resistant parasites as a model for protective immunity in Plasmodium falciparum malaria. Am. J. Trop. Med. Hyg. 69:558563.
36. Dorn, A.,, S. R. Vippagunta,, H. Matile,, C. Jaquet,, J. L. Vennerstrom,, and R. G. Ridley. 1998. An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochem. Pharmacol. 55:727736.
37. Dorsey, G.,, M. R. Kamya,, G. Ndeezi,, J. N. Babirye,, C. R. Phares,, J. E. Olson,, E. T. Katabira,, and P. J. Rosenthal. 2000. Predictors of chloroquine treatment failure in children and adults with falciparum malaria in Kampala, Uganda. Am. J. Trop. Med. Hyg. 62:686692.
38. Dubois, V. L.,, D. F. Platel,, G. Pauly,, and J. Tribouley-Duret. 1995. Plasmodium berghei: implication of intracellular glutathione and its related enzyme in chloroquine resistance in vivo. Exp.Parasitol. 81:117124.
39. Durrand, V.,, A. Berry,, R. Sem,, P. Glaziou,, J. Beaudou,, and T. Fandeur. 2004. Variations in the sequence and expression of the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) and their relationship to chloroquine resistance in vitro. Mol. Biochem. Parasitol. 136:273285.
40. Dzekunov, S. M.,, L. M. B. Ursos,, and P. D. Roepe. 2000. Digestive vacuolar pH of intact intraerythrocytic P. falciparum either sensitive or resistant to chloroquine. Mol. Biochem. Parasitol. 110:107124.
41. Eckstein-Ludwig, U.,, R. J. Webb,, I. D. Van Goethem,, J. M. East,, A. G. Lee,, M. Kimura,, P. M. O’Neill,, P. G. Bray,, S. A. Ward,, and S. Krishna. 2003. Artemisinins target the SERCA of Plasmodium falciparum. Nature 424:957961.
42. Eskelinen, E. L.,, Y. Tanaka,, and P. Saftig. 2003. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 13:137145.
43. Ferdig, M.T.,, R.A. Cooper,, J. Mu,, B. Deng,, D.A. Joy,, X. Z. Su,, and T. E. Wellems. 2004. Dissecting the loci of low-level quinine resistance in malaria parasites. Mol. Microbiol. 52:985997.
44. Ferlan, J. T.,, S. Mookherjee,, I. N. Okezie,, L. Fulgence,, and C. H. Sibley. 2001. Mutagenesis of dihydrofolate reductase from Plasmodium falciparum: analysis in Saccharomyces cerevisiae of triple mutant alleles resistant to pyrimethamine or WR99210. Mol. Biochem. Parasitol. 113:139150.
45. Fidock, D. A.,, and T. E. Wellems. 1997. Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc. Natl. Acad. Sci. USA 94:1093110936.
46. Fidock, D. A.,, T.V. Nguyen,, H. Dodemont,, W. M. Eling,, and A. A. James. 1998. Plasmodium falciparum: identification of the ribosomal P2 protein gene whose expression is independent of the developmentally-regulated rRNAs. Exp. Parasitol. 89:125128.
47. Fidock, D. A.,, T. Nomura,, R. A. Cooper,, X.-Z. Su,, A. K. Talley,, and T. E. Wellems. 2000a. Allelic modifications of the cg2 and cg1 genes do not alter the chloroquine response of drug-resistant Plasmodium falciparum. Mol. Biochem. Parasitol. 110:110.
48. Fidock, D. A.,, T. Nomura,, A. K. Talley,, R. A. Cooper,, S. M. Dzekunov,, M.T. Ferdig,, L. M. Ursos,, A. B. S. Sidhu,, B. Naude,, K. Deitsch,, X.-Z. Su,, J. C. Wootton,, P. D. Roepe,, and T. E. Wellems. 2000b. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6:861871.
49. Fidock, D. A.,, P. J. Rosenthal,, S. L. Croft,, R. Brun,, and S. Nwaka. 2004. Antimalarial drug discovery: efficacy models for compound screening. Nat. Rev. Drug. Discov. 3:509520.
50. Fitch, C. D. 2004. Ferriprotoporphyrin IX, phospholipids,and the antimalarial actions of quinoline drugs. Life Sci. 74:19571972.
51. Flueck, T. P.,, T. Jelinek,, A. H. Kilian,, I. S. Adagu,, G. Kabagambe,, F. Sonnenburg,, and D. C. Warhurst. 2000. Correlation of in vivo-resistance to chloroquine and allelic polymorphisms in Plasmodium falciparum isolates from Uganda. Trop. Med. Int. Health 5:174178.
52. Foote, S. J.,, J. K. Thompson,, A. F. Cowman,, and D. J. Kemp. 1989. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 57:921930.
53. Foote, S. J.,, D. Galatis,, and A. F. Cowman. 1990a. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc. Natl. Acad. Sci. USA 87:30143017.
54. Foote, S. J.,, D. E. Kyle,, R. K. Martin,, A. M. Oduola,, K. Forsyth,, D. J. Kemp,, and A. F. Cowman. 1990b. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 345:255258.
55. Geary, T. G.,, L. C. Bonanni,, J. B. Jensen,, and H. Ginsburg. 1986. Effects of combinations of quinoline-containing antimalarials on Plasmodium falciparum in culture. Ann. Trop. Med. Parasitol. 80:285291.
56. Ginsburg, H.,, O. Famin,, J. Zhang,, and M. Krugliak. 1998. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochem. Pharmacol. 56:13051313.
57. Ginsburg, H.,, S. A. Ward,, and P. G. Bray. 1999. An integrated model of chloroquine action. Parasitol. Today 15:357360.
58. Greenwood, B.,, and T. Mutabingwa. 2002. Malaria in 2002. Nature 415:670672.
59. Gregson, A.,,and C.V. Plowe. 2005. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol. Rev. 57:117145.
60. Hastings, M. D.,, S. J. Bates,, E.A. Blackstone,, S. M. Monks,, T. K. Mutabingwa,, and C. H. Sibley. 2002. Highly pyrimethamine-resistant alleles of dihydrofolate reductase in isolates of Plasmodium falciparum from Tanzania. Trans. R.Soc.Trop.Med.Hyg. 96:674676.
61. Hayton, K.,, and X. Z. Su. 2004. Genetic and biochemical aspects of drug resistance in malaria parasites. Curr.Drug Targets Infect.Disord. 4:110.
62. Homewood, C.A.,, D. C. Warhurst,, W. Peters,, and V. C. Baggaley. 1972. Lysosomes, pH and the antimalarial action of chloroquine. Nature 235:5052.
63. Huaman, M. C.,, N. Roncal,, S. Nakazawa,, T. T. Long,, L. Gerena,, C. Garcia,, L. Solari,, A. J. Magill,, and H. Kanbara. 2004. Polymorphism of the Plasmodium falciparum multidrug resistance and chloroquine resistance transporter genes and in vitro susceptibility to aminoquinolines in isolates from the Peruvian Amazon. Am. J. Trop. Med. Hyg. 70:461466.
64. Hunt, S.Y.,, B. B. Rezvani,, and C. H. Sibley. 2005. Novel alleles of Plasmodium falciparum dhfr that confer resistance to chlorcycloguanil. Mol. Biochem. Parasitol. 139:2532.
65. Hyde, J. E. 2002. Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs. Mol. Biochem. Parasitol. 4:165174.
66. Jack, D. L.,, N. M. Yang,, and M. H. Saier, Jr. 2001. The drug/metabolite transporter superfamily. Eur.J. Biochem. 268:36203639.
67. Jacobs, G. H.,, A. M. Oduola,, D. E. Kyle,, W. K. Milhous,, S. K. Marin,, and M. Aikawa. 1988. Ultrastructural study of the effects of chloroquine and verapmil on Plasmodium falciparum. Am. J. Trop. Med. Hyg. 39:1520.
68. Jensen, N. P.,, A. L. Ager,, R. A. Bliss,, C. J. Canfield,, B. M. Kotecka,, K. H. Rieckmann,, J. Terpinski,, and D. P. Jacobus. 2001. Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials. J. Med. Chem. 44:39253931.
69. Johnson, D. J.,, D.A. Fidock,, M. Mungthin,, V. Lakshmanan,, A. B. S. Sidhu,, P. G. Bray,, and S. A. Ward. 2004. Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol. Cell 15:867877.
70. Kamchonwongpaisan, S.,, R. Quarrell,, N. Charoensetakul,, R. Ponsinet,, T. Vilaivan,, J. Vanichtanankul,, B. Tarnchompoo,, W. Sirawaraporn,, G. Lowe,, and Y. Yuthavong. 2004. Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities. J. Med. Chem. 47:673680.
71. Kirk, K.,, H. A. Horner,, and J. Kirk. 1996. Glucose uptake in Plasmodium falciparum-infected erythrocytes is an equilibrative not an active process. Mol. Biochem. Parasitol. 82:195205.
72. Knighton, D. R.,, C. C. Kan,, E. Howland,, C. A. Janson,, Z. Hostomska,, K. M. Welsh,, and D. A. Matthews. 1994. Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase. Nat. Struct. Biol. 1:186194.
73. Kremsner, P. G.,, S. Winkler,, C. Brandts,, S. Neifer,, U. Bienzle,, and W. Graninger. 1994. Clindamycin in combination with chloroquine or quinine is an effective therapy for uncomplicated Plasmodium falciparum malaria in children from Gabon. J.Infect.Dis. 169:467470.
74. Krishna, S.,, A. C. Uhlemann,, and R. K. Haynes. 2004. Artemisinins: mechanisms of action and potential for resistance. Drug Resist. Updat. 7:233244.
75. Krogstad, D. J.,, P. H. Schlesinger,, and I.Y. Gluzman. 1985. Antimalarials increase vesicle pH in Plasmodium falciparum. J. Cell Biol. 101:23022309.
76. Krogstad, D. J.,, I.Y. Gluzman,, D. E. Kyle,, A. M. Oduola,, S. K. Martin,, W. K. Milhous,, and P. H. Schlesinger. 1987. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238:12831285.
77. Krogstad, D. J.,, and P. H. Schlesinger. 1987. The basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH. Am. J. Trop. Med. Hyg. 36:213220.
78. Krogstad, D. J.,, I. Y. Gluzman,, B. L. Herwaldt,, P. H. Schlesinger,, and T. E. Wellems. 1992. Energy dependence of chloroquine accumulation and chloroquine efflux in Plasmodium falciparum. Biochem. Pharmacol. 43:5762.
79. Krudsood, S.,, M. Imwong,, P. Wilairatana,, S. Pukrittayakamee,, A. Nonprasert,, G. Snounou,, N. J. White,, and S. Looareesuwan. 2005. Artesunate-dapsone-proguanil treatment of falciparum malaria: genotypic determinants of therapeutic response. Trans. R. Soc.Trop. Med. Hyg. 99:142149.
80. Lakshmanan, V.,, P. G. Bray,, D. Verdier-Pinard,, D. J. Johnson,, P. Horrocks,, R. A. Muhle,, G. E. Alakpa,, R. H. Hughes,, D. J. Krogstad,, A. B. S. Sidhu,, and D. A. Fidock. A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J., in press.
81. Lang, T.,, and B. Greenwood. 2003. The development of Lapdap, an affordable new treatment for malaria. Lancet Infect. Dis. 3:162168.
82. Lemcke, T.,, I.T. Christensen,, and F. S. Jorgensen. 1999. Towards an understanding of drug resistance in malaria: three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building. Bioorg. Med. Chem. 7:10031011.
83. Macomber, P. B.,, R. L. O’Brien,, and F. E. Hahn. 1966. Chloroquine: physiological basis of drug resistance in Plasmodium berghei. Science 152:13741375.
84. Martin, R. E.,, and K. Kirk. 2004. The malaria parasite’s chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Mol. Biol. Evol. 21:19381949.
85. Martin, S. K.,, A. M. Oduola,, and W. K. Milhous. 1987. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235:899901.
86. Mawili-Mboumba, D. P.,, J. F. Kun,, B. Lell,, P. G. Kremsner,, and F. Ntoumi. 2002. Pfmdr1 alleles and response to ultralow-dose mefloquine treatment in Gabonese patients. Antimicrob. Agents Chemother. 46:166170.
87. McCutcheon, K. R.,, J. A. Freese,, J. A. Frean,, B. L. Sharp,, and M. B. Markus. 1999. Two mutations in the multidrug-resistance gene homologue of Plasmodium falciparum, pfmdr1, are not useful predictors of in-vivo or in-vitro chloroquine resistance in southern Africa. Trans.R. Soc. Trop. Med. Hyg. 93:300302.
88. Meek, T. D.,, E. P. Garvey,, and D.V. Santi. 1985. Purification and characterization of the bifunctional thymidylate synthetase-dihydrofolate reductase from methotrexate-resistant Leishmania tropica. Biochemistry 24:678686.
89. Mehlotra, R. K.,, H. Fujioka,, P. D. Roepe,, O. Janneh,, L. M. Ursos,, V. Jacobs-Lorena,, D.T. McNamara,, M. J. Bockarie,, J. W. Kazura,, D. E. Kyle,, D. A. Fidock,, and P. A. Zimmerman. 2001. Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America. Proc.Natl.Acad.Sci.USA 98:12689 12694.
90. Mockenhaupt, F. P. 1995. Mefloquine resistance in Plasmodium falciparum. Parasitol.Today 11:248253.
91. Mu, J.,, M.T. Ferdig,, X. Feng,, D.A. Joy,, J. Duan,, T. Furuya,, G. Subramanian,, L. Aravind,, R. A. Cooper,, J. C. Wootton,, M. Xiong,, and X. Z. Su. 2003. Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol. Microbiol. 49:977989.
92. Mutabingwa, T. K.,, C.A. Maxwell,, I. G. Sia,, F. H. Msuya,, S. Mkongewa,, S. Vannithone,, J. Curtis,, and C. F. Curtis. 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. 95:433438.
93. Nagesha, H. S.,, S. Din,, G. J. Casey,, A. I. Susanti,, D. J. Fryauff,, J. C. Reeder,, and A. F. Cowman. 2001. Mutations in the pfmdr1, dhfr and dhps genes of Plasmodium falciparum are associated with in-vivo drug resistance in West Papua, Indonesia. Trans. R. Soc.Trop. Med. Hyg. 95:4349.
94. Nagesha, H. S.,, G. J. Casey,, K. H. Rieckmann,, D. J. Fryauff,, B. S. Laksana,, J. C. Reeder,, J. D. Maguire,, and J. K. Baird. 2003. New haplotypes of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene among chloroquine-resistant parasite isolates. Am. J. Trop. Med. Hyg. 68:398402.
95. Nateghpour, M.,, S. A. Ward,, and R. E. Howells. 1993. Development of halofantrine resistance and determination of cross-resistance patterns in Plasmodium falciparum. Antimicrob. Agents Chemother. 37: 23372343.
96. Naude, B.,, J.A. Brzostowski,, A. R. Kimmel,, and T. E. Wellems. Dictyostelium discoideum expresses a malaria chloroquine resistance mechanism upon transfection with mutant, but not wild-type, Plasmodium falciparum transporter PfCRT. J. Biol.Chem., in press.
97. Nessler, S.,, O. Friedrich,, N. Bakouh,, R. H. Fink,, C. P. Sanchez,, G. Planelles,, and M. Lanzer. 2004. Evidence for activation of endogenous transporters in Xenopus laevis oocytes expressing the Plasmodium falciparum chloroquine resistance transporter, PfCRT. J. Biol. Chem. 279:3943839446.
98. Ngo, T.,, M. Duraisingh,, M. Reed,, D. Hipgrave,, B. Biggs,, and A. F. Cowman. 2003. Analysis of pfcrt, pfmdr1, dhfr, and dhps mutations and drug sensitivities in Plasmodium falciparum isolates from patients in Vietnam before and after treatment with artemisinin. Am. J. Trop. Med. Hyg. 68:350356.
99. Nosten, F.,, F. ter Kuile,, T. Chongsuphajaisiddhi,, C. Luxemburger,, H. K. Webster,, M. Edstein,, L. Phaipun,, K. L. Thew,, and N. J. White. 1991. Mefloquine-resistant falciparum malaria on the Thai-Burmese border. Lancet 337:11401143.
100. Nosten, F.,, M. van Vugt,, R. Price,, C. Luxemburger,, K. L. Thway,, A. Brockman,, R. Mc Gready,, F. ter Kuile,, S. Looareesuwan,, and N. J. White. 2000. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet 356:297302.
101. O’Neil, R. H.,, R. H. Lilien,, B. R. Donald,, R. M. Stroud,, and A. C. Anderson. 2003. The crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveals a novel architecture for the bifunctional enzyme. J. Eukaryot. Microbiol. 50(Suppl):555556.
102. O’Neill, P. M.,, and G. H. Posner. 2004. A medicinal chemistry perspective on artemisinin and related endoperoxides. J. Med. Chem. 47:29452964.
103. Pagola, S.,, P.W. Stephens,, D. S. Bohle,, A. D. Kosar,, and S. K. Madsen. 2000. The structure of malaria pigment beta-haematin. Nature 404:307310.
104. Peters, W. 1970. Chemotherapy and Drug Resistance in Malaria.Academic Press,London,United Kingdom.
105. Peters, W.,, R. E. Howells,, J. Portus,, B. L. Robinson,, S. Thomas,, and D. C. Warhurst. 1977. The chemotherapy of rodent malaria, XXVII. Studies on mefloquine (WR 142,490). Ann. Trop. Med. Parasitol. 71:407418.
106. Peterson, D. S.,, D. Walliker,, and T. E. Wellems. 1988. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc. Natl.Acad. Sci. USA 85:91149118.
107. Peterson, D. S.,, W. K. Milhous,, and T. E. Wellems. 1990. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc.Natl.Acad. Sci. USA 87:30183022.
108. Pickard, A. L.,, C. Wongsrichanalai,, A. Purfield,, D. Kamwendo,, K. Emery,, C. Zalewski,, F. Kawamoto,, R. S. Miller,, and S. R. Meshnick. 2003. Resistance to antimalarials in southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob. Agents Chemother. 47:24182423.
109. Pillai, D. R.,, G. Hijar,, Y. Montoya,, W. Marouino,, T. K. Ruebush II,, C. Wongsrichanalai,, and K. C. Kain. 2003. Lack of prediction of mefloquine and mefloquine-artesunate treatment outcome by mutations in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene for P. falciparum malaria in Peru. Am. J. Trop. Med. Hyg. 68:107110.
110. Plowe, C. V.,, J. F. Cortese,, A. Djimdé,, O. C. Nwanyanwu,, W. M. Watkins,, P.A. Winstanley,, J. G. Estrada-Franco,, R. E. Mollinedo,, J. C. Avila,, J. L. Cespedes,, D. Carter,, and O. K. Doumbo. 1997. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J. Infect. Dis. 176:15901596.
111. Povoa, M. M.,, I. S. Adagu,, S. G. Oliveira,, R. L. Machado,, M. A. Miles,, and D. C. Warhurst. 1998. Pfmdr1 Asn1042Asp and Asp1246Tyr polymorphisms, thought to be associated with chloroquine resistance, are present in chloroquine-resistant and -sensitive Brazilian field isolates of Plasmodium falciparum. Exp. Parasitol. 88:6468.
112. Price, R.,, G. Robinson,, A. Brockman,, A. Cowman,, and S. Krishna. 1997. Assessment of pfmdr1 gene copy number by tandem competitive polymerase chain reaction. Mol. Biochem. Parasitol. 85:161169.
113. Price, R.,, F. Nosten,, J. A. Simpson,, C. Luxemburger,, L. Phaipun,, F. ter Kuile,, M. van Vugt,, T. Chongsuphajaisiddhi,, and N. J. White. 1999a. Risk factors for gametocyte carriage in uncomplicated falciparum malaria. Am. J. Trop. Med. Hyg. 60:10191023.
114. Price, R. N.,, C. Cassar,, A. Brockman,, M. Duraisingh,, M. van Vugt,, N. J. White,, F. Nosten,, and S. Krishna. 1999b.The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob. Agents Chemother. 43:29432949.
115. Price, R. N.,, A.-C. Uhlemann,, A. Brockman,, R. Mc Gready,, E. Ashley,, L. Phaipun,, R. Patel,, K. Laing,, S. Looareesuwan,, N. J. White,, F. Nosten,, and S. Krishna. 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364:438447.
116. Pukrittayakamee, S.,, A. Chantra,, S. Vanijanonta,, R. Clemens,, S. Looareesuwan,, and N. J. White. 2000. Therapeutic responses to quinine and clindamycin in multidrug-resistant falciparum malaria. Antimicrob. Agents Chemother. 44:23952398.
117. Rastelli, G.,, W. Sirawaraporn,, P. Sompornpisut,, T. Vilaivan,, S. Kamchonwongpaisan,, R. Quarrell,, G. Lowe,, Y. Thebtaranonth,, and Y. Yuthavong. 2000. Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: structural basis of antifolate resistance. Bioorg. Med. Chem. 8:11171128.
118. Raynes, K.,, M. Foley,, L. Tilley,, and L.W. Deady. 1996. Novel bisquinoline antimalarials. Synthesis, antimalarial activity, and inhibition of haem polymerisation. Biochem. Pharmacol. 52:551559.
119. Reed, M. B.,, K. J. Saliba,, S. R. Caruana,, K. Kirk,, and A. F. Cowman. 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403:906909.
120. Reynolds, M. G.,, and D. S. Roos. 1998. A biochemical and genetic model for parasite resistance to antifolates. Toxoplasma gondii provides insights into pyrimethamine and cycloguanil resistance in Plasmodium falciparum. J. Biol. Chem. 273:34613469.
121. Roper, C.,, R. Pearce,, S. Nair,, B. Sharp,, F. Nosten,, and T. Anderson. 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305:1124.
122. Sachs, J. D. 2005. Achieving the Millennium Development Goals: the case of malaria. N. Engl. J. Med. 352:115117.
123. Saliba, K. J.,, P. I. Folb,, and P. J. Smith.1998. Role for the Plasmodium falciparum digestive vacuole in chloroquine resistance.Biochem.Pharmacol. 56:313320.
124. Sanchez, C. P.,, S. Wunsch,, and M. Lanzer. 1997. Identification of a chloroquine importer in Plasmodium falciparum.Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype. J. Biol. Chem. 272:26522658.
125. Sanchez, C. P.,, W. Stein,, and M. Lanzer. 2003. trans stimulation provides evidence for a drug efflux carrier as the mechanism of chloroquine resistance in Plasmodium falciparum. Biochemistry 42:93839394.
126. Sanchez, C. P.,, J. E. McLean,, W. Stein,, and M. Lanzer. 2004. Evidence for a substrate specific and inhibitable drug efflux system in chloroquine resistant Plasmodium falciparum strains. Biochemistry 43: 1636516373.
127. Sardarian, A.,, K.T. Douglas,, M. Read,, P. F. Sims,, J. E. Hyde,, P. Chitnumsub,, R. Sirawaraporn,, and W. Sirawaraporn. 2003. Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites. Org. Biomol. Chem. 1:960964.
128. Shallom, S.,, K. Zhang,, L. Jiang,, and P. K. Rathod. 1999. Essential protein-protein interactions between Plasmodium falciparum thymidylate synthase and dihydrofolate reductase domains. J. Biol. Chem. 274:3778137786.
129. Shviro, Y.,, and N. Shaklai. 1987. Glutathione as a scavenger of free hemin. A mechanism of preventing red cell membrane damage. Biochem. Pharmacol. 36:38013807.
130. Sidhu, A. B. S.,, D. Verdier-Pinard,, and D. A. Fidock. 2002. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298:210213.
131. Sidhu, A. B. S.,, S. G. -Valderramos,, and D. A. Fidock. pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Mol.Microbiol.,in press.
132. Sina, B. 2002.Focus on Plasmodium vivax. Trends Parasitol. 18:287289.
133. Sirawaraporn, W.,, T. Sathitkul,, R. Sirawaraporn,, Y. Yuthavong,, and D. V. Santi. 1997a. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. USA 94:11241129.
134. Sirawaraporn, W.,, S. Yongkiettrakul,, R. Sirawaraporn,, Y. Yuthavong,, and D.V. Santi. 1997b. Plasmodium falciparum: asparagine mutant at residue 108 of dihydrofolate reductase is an optimal antifolate-resistant single mutant. Exp. Parasitol. 87:245252.
135. Skinner-Adams, T.,, and T. M. Davis. 1999. Synergistic in vitro antimalarial activity of omeprazole and quinine.Antimicrob.Agents Chemother. 43:13041306.
136. Slater, A. F.,, and A. Cerami. 1992. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167169.
137. Su, X.-Z.,, L. S. Kirkman,, and T. E. Wellems. 1997. Complex polymorphisms in a ~330 kDa protein are linked to chloroquine-resistant P. falciparum in southeast Asia and Africa. Cell 91:593603.
138. Sullivan, D. J., Jr.,, I.Y. Gluzman,, D. G. Russell,, and D. E. Goldberg. 1996. On the molecular mechanism of chloroquine’s antimalarial action. Proc.Natl. Acad. Sci. USA 93:1186511870.
139. Sutherland, C. J.,, A. Alloueche,, J. Curtis,, C. J. Drakeley,, R. Ord,, M. Duraisingh,, B. M. Greenwood,, M. Pinder,, D. C. Warhurst,, and G. A. Targett. 2002. Gambian children successfully treated with chloroquine can harbour and transmit Plasmodium falciparum gametocytes carrying resistance genes. Am. J. Trop. Med. Hyg. 67:578585.
140. Thaithong, S.,, L. C. Ranford-Cartwright,, N. Siripoon,, P. Harnyuttanakorn,, N. S. Kanchanakhan,, A. Seugorn,, K. Rungsihirunrat,, P.V. Cravo,,and G.H. Beale. 2001. Plasmodium falciparum: gene mutations and amplification of dihydrofolate reductase genes in parasites grown in vitro in presence of pyrimethamine. Exp. Parasitol. 98:5970.
141. Tran, C.V.,, and M. H. Saier, Jr. 2004. The principal chloroquine resistance protein of Plasmodium falciparum is a member of the drug/metabolite transporter superfamily. Microbiology 150:13.
142. Tran, T. H.,, C. Dolecek,, P. M. Pham,, T. D. Nguyen,, T.T. Nguyen,, H. T. Le,, T. H. Dong,, T. T. Tran,, K. Stepniewska,, N. J. White,, and J. Farrar. 2004. Dihydroartemisinin-piperaquine against multidrugresistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet 363:1822.
143. Trape, J. F. 2001. The public health impact of chloroquine resistance in Africa. Am. J. Trop. Med. Hyg. 64:1217.
144. Triglia, T.,, S. J. Foote,, D. J. Kemp,, and A. F. Cowman. 1991. Amplification of the multidrug resistance gene pfmdr1 in Plasmodium falciparum has arisen as multiple independent events.Mol.Cell.Biol. 11:52445250.
145. Triglia, T.,, J. G. Menting,, C. Wilson,, and A. FCowman. 1997. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc.Natl.Acad. Sci. USA 94:1394413949.
146. Trujillo, M.,, R. G. Donald,, D. S. Roos,, P. J. Greene,, and D. V. Santi. 1996. Heterologous expression and characterization of the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of Toxoplasma gondii. Biochemistry 35:63666374.
147. Uhlemann, A. C.,, A. Cameron,, U. Eckstein-Ludwig,, W.-Y. Ho,, W. C. Chan,, J. Fischbarg,, PIserovich,, F.A. Zuniga,, M. East,, A. Lee,, L. Brady,, R. K. Haynes,, and S. Krishna. A single amino acid residue can determine sensitivity of SERCAs to artemisinins. Nature Struct. Mol. Biol., in press.
148. Ursos, L. M.,, and P. D. Roepe. 2002. Chloroquine resistance in the malarial parasite, Plasmodium falciparum. Med. Res. Rev. 22:465491.
149. Waller, K. L.,, R. A. Muhle,, L. M. Ursos,, P. Horrocks,, D. Verdier-Pinard,, A. B. Sidhu,, H. Fujioka,, P. D. Roepe,, and D. A. Fidock. 2003. Chloroquine resistance modulated in vitro by expression levels of the Plasmodium falciparum chloroquine resistance transporter. J.Biol. Chem.278:3359333601.
150. Waller, K. L.,, S. Lee,, and D. A. Fidock,. 2004. Molecular and cellular biology of chloroquine resistance in Plasmodium falciparum, p. 501540. In A. P. Waters, and C. J. Janse (ed.), Malaria Parasites: Genomes and Molecular Biology. Caister Academic Press, Wymondham, United Kingdom.
151. Wang, P.,, R. K. Brobey,, T. Horii,, P. F. Sims,, and J. E. Hyde. 1999. Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy. Mol. Microbiol. 32:12541262.
152. Wang, P.,, N. Nirmalan,, Q. Wang,, P. F. Sims,, and J. E. Hyde. 2004. Genetic and metabolic analysis of folate salvage in the human malaria parasite Plasmodium falciparum. Mol. Biochem. Parasitol. 135:7787.
153. Warhurst, D. C. 2002. Resistance to antifolates in Plasmodium falciparum, the causative agent of tropical malaria. Sci. Prog. 85:89111.
154. Warhurst, D. C.,, J. C. Craig,, and I. S. Adagu. 2002. Lysosomes and drug resistance in malaria. Lancet 360:15271529.
155. Watkins, W. M.,, and M. Mosobo. 1993. Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine:selective pressure for resistance is a function of long elimination half-life. Trans. R. Soc. Trop. Med. Hyg. 87:7578.
156. Watt, G.,, L. Loesuttivibool,, G. D. Shanks,, E. F. Boudreau,, A. E. Brown,, K. Pavanand,, H. K. Webster,, and S. Wechgritaya. 1992. Quinine with tetracycline for the treatment of drug-resistant falciparum malaria in Thailand. Am. J. Trop. Med. Hyg. 47:108111.
157. Wattanarangsan, J.,, S. Chusacultanachai,, J. Yuvaniyama,, S. Kamchonwongpaisan,, and Y. Yuthavong. 2003. Effect of N-terminal truncation of Plasmodium falciparum dihydrofolate reductase on dihydrofolate reductase and thymidylate synthase activity. Mol. Biochem. Parasitol. 126:97102.
158. Wellems, T. E.,, L. J. Panton,, I. Y. Gluzman,, V. E. do Rosario,, R. W. Gwadz,, A. Walker-Jonah,, and D. J. Krogstad. 1990. Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345:253255.
159. Wellems, T. E.,, A. Walker-Jonah,, and L.J. Panton. 1991. Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc. Natl. Acad. Sci. USA 88:33823386.
160. Wellems, T. E.,, and C.V. Plowe. 2001. Chloroquineresistant malaria. J. Infect. Dis. 184:770776.
161. White, N. J. 1996. The treatment of malaria. N. Engl. J. Med. 335:800806.
162. White, N. J.,, and W. Pongtavornpinyo. 2003. The de novo selection of drug-resistant malaria parasites. Proc. R. Soc. Lond. B Biol. Sci. 270:545554.
163. White, N. J. 2004.Antimalarial drug resistance. J. Clin. Investig. 113:10841092.
164. Wilson, C. M.,, A. E. Serrano,, A. Wasley,, M. P. Bogenschutz,, A. H. Shankar,, and D. F. Wirth. 1989. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 244:11841186.
165. Wilson, C. M.,, S. K. Volkman,, S. Thaithong,, R. K. Martin,, D. E. Kyle,, W. K. Milhous,, and D. F. Wirth. 1993. Amplification of pfmdr1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand. Mol. Biochem. Parasitol. 57:151160.
166. Winstanley, P. 2001. Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria. Trop. Med. Int. Health 6:952954.
167. Wissing, F.,, C. P. Sanchez,, P. Rohrbach,, S. Ricken,, and M. Lanzer. 2002. Illumination of the malaria parasite Plasmodium falciparum alters intracellular pH. Implications for live cell imaging. J. Biol. Chem. 277:3774737755.
168. Wongsrichanalai, C.,, A. L. Pickard,, W. H. Wernsdorfer,, and S. R. Meshnick. 2002. Epidemiology of drug-resistant malaria. Lancet Infect.Dis. 2:209218.
169. Wood, P. A.,, and J. W. Eaton. 1993. Hemoglobin catabolism and host-parasite heme balance in chloroquine-sensitive and chloroquine-resistant Plasmodium berghei infections. Am. J. Trop. Med. Hyg. 48:465472.
170. Wooden, J. M.,, L. H. Hartwell,, B. Vasquez,, and C. H. Sibley. 1997. Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum. Mol.Biochem. Parasitol. 85:2540.
171. Wootton, J. C.,, X. Feng,, M. T. Ferdig,, R. A. Cooper,, J. Mu,, D. I. Baruch,, A. J. Magill,, and X. Z. Su. 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418:320323.
172. World Health Organization. 2001. Drug resistance in malaria.WHO/CDC/CSR/DRS/2001.4.
173. Wu, Y.,, L. A. Kirkman,, and T. E. Wellems. 1996. Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine. Proc.Natl.Acad. Sci. USA 93:11301134.
174. Yayon, A.,, Z. I. Cabantchik,, and H. Ginsburg. 1984. Identification of the acidic compartment of Plasmodium falciparum-infected human erythrocytes as the target of the antimalarial drug chloroquine. EMBO J. 3:26952700.
175. Yayon, A. 1985. The antimalarial mode of action of chloroquine. Rev. Clin. Basic Pharm. 5:99139.
176. Yeung, S.,, W. Pongtavornpinyo,, I. M. Hastings,, A. J. Mills,, and N. J. White. 2004. Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. Am. J. Trop. Med. Hyg. 71: 179186.
177. Yuthavong, Y.,, T. Vilaivan,, N. Chareonsethakul,, S. Kamchonwongpaisan,, W. Sirawaraporn,, R. Quarrell,, and G. Lowe. 2000. Development of a lead inhibitor for theA16VS108T mutant of dihydrofolate reductase from the cycloguanil-resistant strain (T9/94) of Plasmodium falciparum. J. Med. Chem. 43:27382744.
178. Yuthavong, Y. 2002.Basis for antifolate action and resistance in malaria. Microbes Infect. 4:175182.
179. Yuthavong, Y.,, J. Yuvaniyama,, P. Chitnumsub,, J. Vanichtanankul,, S. Chusacultanachai,, B. Tarnchompoo,, T. Vilaivan,, and S. Kamchonwongpaisan. 2005. Malaria (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors. Parasitology 130:249259.
180. Yuvaniyama, J.,, P. Chitnumsub,, S. Kamchonwongpaisan,, J. Vanichtanankul,, W. Sirawaraporn,, P. Taylor,, M. D. Walkinshaw,, and Y. Yuthavong. 2003. Insights into antifolate resistance from malarial DHFR-TS structures. Nat. Struct. Biol. 10:357365.
181. Zalis, M. G.,, L. Pang,, M. S. Silveira,, W. K. Milhous,, and D. F. Wirth. 1998. Characterization of Plasmodium falciparum isolated from the Amazon region of Brazil: evidence for quinine resistance. Am. J.Trop. Med. Hyg. 58:630637.
182. Zhang, H.,, E. M. Howard,, and P. D. Roepe. 2002. Analysis of the antimalarial drug resistance protein Pfcrt expressed in yeast. J. Biol. Chem. 277:4976749775.
183. Zhang, H.,, M. Paguio,, and P. D. Roepe. 2004. The antimalarial drug resistance protein Plasmodium falciparum chloroquine resistance transporter binds chloroquine. Biochemistry 43:82908296.
184. Zhang, J.,, M. Krugliak,, and H. Ginsburg. 1999. The fate of ferriprotorphyrin IX in malaria infected erythrocytes in conjunction with the mode of action of antimalarial drugs. Mol. Biochem. Parasitol. 99:129141.
185. Zhang, K.,, and P. K. Rathod. 2002. Divergent regulation of dihydrofolate reductase between malaria parasite and human host. Science 296:545547.

Tables

Generic image for table
TABLE 1

allelic variants identified in field isolates and laboratory-adapted lines

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error