Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross

Molecular Microbiology

Volumn 78, Issue 3, 2010, Pages 770-787

  Patel, Jigar J ^a,b   Thacker, Drew ^a,c   Tan, John C ^a   Pleeter, Perri ^d   Checkley, Lisa ^a   Gonzales, Joseph M ^a   Deng, Bingbing ^a,e   Roepe, Paul D ^d   Cooper, Roland A ^f   Ferdig, Michael T ^a  

^a UNIVERSITY OF NOTRE DAME   (United States)

^b Roche NimbleGen Inc   (United States)

^c MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^d GEORGETOWN UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e Sanaria ^*  (United States)

^f OLD DOMINION UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMITRIPTYLINE; CARRIER PROTEIN; CHLOROQUINE; CHLORPHENIRAMINE; CITALOPRAM; CYPROHEPTADINE; DESIPRAMINE; GLYCOPROTEIN P; KETOTIFEN; MULTIDRUG RESISTANCE PROTEIN 1; PLASMODIUM FALCIPARUM CHLOROQUINE RESISTANCE TRANSPORTER; PROBENECID; RECOMBINANT PROTEIN; UNCLASSIFIED DRUG; VERAPAMIL;

ALLELE; ANTIBIOTIC SENSITIVITY; ARTICLE; CHEMOSENSITIZATION; CHROMOSOME 7; CLONE; COMPETITIVE INHIBITION; CONTROLLED STUDY; COPY NUMBER VARIATION; DRUG ANTAGONISM; DRUG POTENTIATION; GENE IDENTIFICATION; GENE INTERACTION; GENE LOCUS; GENE MUTATION; GENOTYPE; HAPLOTYPE; IC 50; MICROBIAL GROWTH; NONHUMAN; PHOTOAFFINITY LABELING; PLASMODIUM FALCIPARUM; PRIORITY JOURNAL; PROGENY; PROTEIN PROTEIN INTERACTION; PROTEIN PURIFICATION; PROTOZOAL GENETICS; QUANTITATIVE TRAIT LOCUS MAPPING; SOUTHEAST ASIA;

ANTIMALARIALS; CHLOROQUINE; DRUG RESISTANCE; GENE DOSAGE; MEMBRANE TRANSPORT PROTEINS; MUTATION; PLASMODIUM FALCIPARUM; PROTOZOAN PROTEINS; QUANTITATIVE TRAIT LOCI; VERAPAMIL;

PLASMODIUM FALCIPARUM;

EID: 77958551656     PISSN: 0950382X     EISSN: 13652958     Source Type: Journal    
DOI: 10.1111/j.1365-2958.2010.07366.x     Document Type: Article

References (105)

1. Adagu, I.S., and Warhurst, D.C. (2001) Plasmodium falciparum: linkage disequilibrium between loci in chromosomes 7 and 5 and chloroquine selective pressure in Northern Nigeria. Parasitology 123: 219-224.
2. Adovelande, J., Deleze, J., and Schrevel, J. (1998) Synergy between two calcium channel blockers, verapamil and fantofarone (SR33557), in reversing chloroquine resistance in Plasmodium falciparum. Biochem Pharmacol 55: 433-440.
3. Amoah, L.E., Lekostaj, J.K., and Roepe, P.D. (2007) Heterologous expression and ATPase activity of mutant versus wild type PfMDR1 protein. Biochemistry 46: 6060-6073.
4. Babiker, H.A., Pringle, S.J., Abdel-Muhsin, A., Mackinnon, M., Hunt, P., and Walliker, D. (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: 1535-1538.
5. Barnes, D.A., Foote, S.J., Galatis, D., Kemp, D.J., and Cowman, A.F. (1992) Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum. EMBO J 11: 3067-3075.
6. Bennett, T.N., Kosar, A.D., Ursos, L.M., Dzekunov, S., Singh Sidhu, A.B., Fidock, D.A., and Roepe, P.D. (2004) Drug resistance-associated pfCRT mutations confer decreased Plasmodium falciparum digestive vacuolar pH. Mol Biochem Parasitol 133: 99-114.
7. Best Plummer, W., Pinto Pereira, L.M., and Carrington, C.V. (2004) Pfcrt and pfmdr1 alleles associated with chloroquine resistance in Plasmodium falciparum from Guyana, South America. Mem Inst Oswaldo Cruz 99: 389-392.
8. Bhattacharjee, A.K., Kyle, D.E., and Vennerstrom, J.L. (2001) Structural analysis of chloroquine resistance reversal by imipramine analogs. Antimicrob Agents Chemother 45: 2655-2657.
9. Bhattacharjee, A.K., Kyle, D.E., Vennerstrom, J.L., and Milhous, W.K. (2002) A 3D QSAR pharmacophore model and quantum chemical structure - activity analysis of chloroquine (CQ)-resistance reversal. J Chem Inf Comput Sci 42: 1212-1220.
10. Bray, P.G., and Ward, S.A. (1998) A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum. Pharmacol Ther 77: 1-28.
11. Bray, P.G., Mungthin, M., Ridley, R.G., and Ward, S.A. (1998) Access to hematin: the basis of chloroquine resistance. Mol Pharmacol 54: 170-179.
12. Bray, P.G., Deed, S., Fox, E., Kalkanidis, M., Mungthin, M., Deady, L.W., and Tilley, L. (2005) Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum. Biochem Pharmacol 70: 1158-1166.
13. Brockman, A., Price, R.N., Van Vugt, M., Heppner, D.G., Walsh, D., Sookto, P., et al. (2000) Plasmodium falciparum antimalarial drug susceptibility on the north-western border of Thailand during five years of extensive use of artesunate-mefloquine. Trans R Soc Trop Med Hyg 94: 537-544.
14. Broman, K.W., Wu, H., Sen, S., and Churchill, G.A. (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19: 889-890.
15. Campbell, C.C., Collins, W.E., Nguyen-Dinh, P., Barber, A., and Broderson, J.R. (1982) Plasmodium falciparum gametocytes from culture in vitro develop to sporozoites that are infectious to primates. Science 217: 1048-1050.
16. Chavchich, M., Gerena, L., Peters, J., Chen, N., Cheng, Q., and Kyle, D.E. (2010) Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum. Antimicrob Agents Chemother 54: 2455-2464.
17. Chen, N., Russell, B., Fowler, E., Peters, J., and Cheng, Q. (2002) Levels of chloroquine resistance in Plasmodium falciparum are determined by loci other than pfcrt and pfmdr1. J Infect Dis 185: 405-407.
18. Chen, N., Kyle, D.E., Pasay, C., Fowler, E.V., Baker, J., Peters, J.M., and Cheng, Q. (2003) pfcrt Allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum isolates from the Philippines. Antimicrob Agents Chemother 47: 3500-3505.
19. Chen, N., Chavchich, M., Peters, J.M., Kyle, D.E., Gatton, M.L., and Cheng, Q. (2010) Deamplification of pfmdr1-containing amplicon on chromosome 5 in Plasmodium falciparum is associated with reduced resistance to artelinic acid in vitro. Antimicrob Agents Chemother 54: 3395-3401.
20. Contreras, C.E., Cortese, J.F., Caraballo, A., and Plowe, C.V. (2002) Genetics of drug-resistant Plasmodium falciparum malaria in the Venezuelan state of Bolivar. Am J Trop Med Hyg 67: 400-405.
21. Cooper, R.A., Ferdig, M.T., Su, X.Z., Ursos, L.M., Mu, J., Nomura, T., et al. (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: 35-42.
22. Cowman, A.F., Galatis, D., and Thompson, J.K. (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: 1143-1147.
23. Djimde, A., Doumbo, O.K., Cortese, J.F., Kayentao, K., Doumbo, S., Diourte, Y., et al. (2001) A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257-263.
24. Doerge, R.W., and Churchill, G.A. (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142: 285-294.
25. Duraisingh, M.T., and Cowman, A.F. (2005) Contribution of the pfmdr1 gene to antimalarial drug-resistance. Acta Trop 94: 181-190.
26. Durrand, V., Berry, A., Sem, R., Glaziou, P., Beaudou, J., and Fandeur, T. (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: 273-285.
27. Elion, G.B., Singer, S., and Hitchings, G.H. (1954) Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolites. J Biol Chem 208: 477-488.
28. Ferdig, M.T., Cooper, R.A., Mu, J., Deng, B., Joy, D.A., Su, X.Z., and Wellems, T.E. (2004) Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol 52: 985-997.
29. Fidock, D.A., Nomura, T., Talley, A.K., Cooper, R.A., Dzekunov, S.M., Ferdig, M.T., et al. (2000) Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6: 861-871.
30. Foote, S.J., Thompson, J.K., Cowman, A.F., and Kemp, D.J. (1989) Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 57: 921-930.
31. Foote, S.J., Kyle, D.E., Martin, R.K., Oduola, A.M., Forsyth, K., Kemp, D.J., and Cowman, A.F. (1990) Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 345: 255-258.
32. Fritz, F., Howard, E.M., Hoffman, M.M., and Roepe, P.D. (1999) Evidence for altered ion transport in Saccharomyces cerevisiae overexpressing human MDR 1 protein. Biochemistry 38: 4214-4226.
33. Gerena, L., Bass, G.T., Sr, Kyle, D.E., Oduola, A.M., Milhous, W.K., and Martin, R.K. (1992) Fluoxetine hydrochloride enhances in vitro susceptibility to chloroquine in resistant Plasmodium falciparum. Antimicrob Agents Chemother 36: 2761-2765.
34. Ginsburg, H. (2005) Should chloroquine be laid to rest? Acta Trop 96: 16-23.
35. Hastings, I.M., Bray, P.G., and Ward, S.A. (2002) Parasitology. A requiem for chloroquine. Science 298: 74-75.
36. Hayton, K., and Su, X.Z. (2004) Genetic and biochemical aspects of drug resistance in malaria parasites. Curr Drug Targets Infect Disord 4: 1-10.
37. Hayward, R., Saliba, K.J., and Kirk, K. (2005) pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum. Mol Microbiol 55: 1285-1295.
38. Johnson, D.J., Fidock, D.A., Mungthin, M., Lakshmanan, V., Sidhu, A.B., Bray, P.G., and Ward, S.A. (2004) Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol Cell 15: 867-877.
39. Krogstad, D.J., Gluzman, I.Y., Kyle, D.E., Oduola, A.M., Martin, S.K., Milhous, W.K., and Schlesinger, P.H. (1987) Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238: 1283-1285.
40. Kublin, J.G., Cortese, J.F., Njunju, E.M., Mukadam, R.A., Wirima, J.J., Kazembe, P.N., et al. (2003) Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 187: 1870-1875.
41. Kyle, D.E., Oduola, A.M., Martin, S.K., and Milhous, W.K. (1990) Plasmodium falciparum: modulation by calcium antagonists of resistance to chloroquine, desethylchloroquine, quinine, and quinidine in vitro. Trans R Soc Trop Med Hyg 84: 474-478.
42. Lakshmanan, V., Bray, P.G., Verdier-Pinard, D., Johnson, D.J., Horrocks, P., Muhle, R.A., et al. (2005) A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J 24: 2294-2305.
43. Laufer, M.K., Takala-Harrison, S., Dzinjalamala, F.K., Stine, O.C., Taylor, T.E., and Plowe, C.V. (2010) Return of chloroquine-susceptible falciparum malaria in Malawi was a reexpansion of diverse susceptible parasites. J Infect Dis 202: 801-808.
44. Lehane, A.M., and Kirk, K. (2010) Efflux of a range of antimalarial drugs and 'chloroquine resistance reversers' from the digestive vacuole in malaria parasites with mutant PfCRT. Mol Microbiol 77: 1039-1051.
45. Lekostaj, J.K., Amoah, L.E., and Roepe, P.D. (2008a) A single S1034C mutation confers altered drug sensitivity to PfMDR1 ATPase activity that is characteristic of the 7G8 isoform. Mol Biochem Parasitol 157: 107-111.
46. Lekostaj, J.K., Natarajan, J.K., Paguio, M.F., Wolf, C., and Roepe, P.D. (2008b) Photoaffinity labeling of the Plasmodium falciparum chloroquine resistance transporter with a novel perfluorophenylazido chloroquine. Biochemistry 47: 10394-10406.
47. Lim, A.S., and Cowman, A.F. (1996) Plasmodium falciparum: chloroquine selection of a cloned line and DNA rearrangements. Exp Parasitol 83: 283-294.
48. Liu, D., Cai, X., Ren, D., Liu, R., Lin, S., Zeng, L., and Tang, X. (1999) [Changes in chloroquine resistance of Plasmodium falciparum in Hainan province]. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 17: 32-34.
49. Looareesuwan, S., Kyle, D.E., Viravan, C., Vanijanonta, S., Wilairatana, P., Charoenlarp, P., et al. (1992) Treatment of patients with recrudescent falciparum malaria with a sequential combination of artesunate and mefloquine. Am J Trop Med Hyg 47: 794-799.
50. McGrath, T., Latoud, C., Arnold, S.T., Safa, A.R., Felsted, R.L., and Center, M.S. (1989) Mechanisms of multidrug resistance in HL60 cells. Analysis of resistance associated membrane proteins and levels of mdr gene expression. Biochem Pharmacol 38: 3611-3619.
51. Martin, R.E., Marchetti, R.V., Cowan, A.I., Howitt, S.M., Broer, S., and Kirk, K. (2009) Chloroquine transport via the malaria parasite's chloroquine resistance transporter. Science 325: 1680-1682.
52. Martin, S.K., Oduola, A.M., and Milhous, W.K. (1987) Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235: 899-901.
53. Martiney, J.A., Cerami, A., and Slater, A.F. (1995) Verapamil reversal of chloroquine resistance in the malaria parasite Plasmodium falciparum is specific for resistant parasites and independent of the weak base effect. J Biol Chem 270: 22393-22398.
54. Masseno, V., Muriithi, S., and Nzila, A. (2009) In vitro chemosensitization of Plasmodium falciparum to antimalarials by verapamil and probenecid. Antimicrob Agents Chemother 53: 3131-3134.
55. Mehlotra, R.K., Fujioka, H., Roepe, P.D., Janneh, O., Ursos, L.M., Jacobs-Lorena, V., et al. (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.
56. Menezes, C.M., Kirchgatter, K., Di Santi, S.M., Savalli, C., Monteiro, F.G., Paula, G.A., and Ferreira, E.I. (2002) In vitro chloroquine resistance modulation study on fresh isolates of Brazilian Plasmodium falciparum: intrinsic antimalarial activity of phenothiazine drugs. Mem Inst Oswaldo Cruz 97: 1033-1039.
57. Menezes, C.M., Kirchgatter, K., Di Santi, S.M., Savalli, C., Monteiro, F.G., Paula, G.A., and Ferreira, E.I. (2003) In vitro evaluation of verapamil and other modulating agents in Brazilian chloroquine-resistant Plasmodium falciparum isolates. Rev Soc Bras Med Trop 36: 5-9.
58. Mita, T., Kaneko, A., Lum, J.K., Bwijo, B., Takechi, M., Zungu, I.L., et al. (2003) Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. Am J Trop Med Hyg 68: 413-415.
59. Mittra, P., Vinayak, S., Chandawat, H., Das, M.K., Singh, N., Biswas, S., et al. (2006) Progressive increase in point mutations associated with chloroquine resistance in Plasmodium falciparum isolates from India. J Infect Dis 193: 1304-1312.
60. Mu, J., Ferdig, M.T., Feng, X., Joy, D.A., Duan, J., Furuya, T., et al. (2003) Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol Microbiol 49: 977-989.
61. Mu, J., Awadalla, P., Duan, J., McGee, K.M., Joy, D.A., McVean, G.A., and Su, X.Z. (2005) Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol 3: e335.
62. Nzila, A., Mberu, E., Bray, P., Kokwaro, G., Winstanley, P., Marsh, K., and Ward, S. (2003) Chemosensitization of Plasmodium falciparum by probenecid in vitro. Antimicrob Agents Chemother 47: 2108-2112.
63. Orjih, A.U., Ryerse, J.S., and Fitch, C.D. (1994) Hemoglobin catabolism and the killing of intraerythrocytic Plasmodium falciparum by chloroquine. Experientia 50: 34-39.
64. Osman, M.E., Mockenhaupt, F.P., Bienzle, U., Elbashir, M.I., and Giha, H.A. (2007) Field-based evidence for linkage of mutations associated with chloroquine (pfcrt/pfmdr1) and sulfadoxine-pyrimethamine (pfdhfr/pfdhps) resistance and for the fitness cost of multiple mutations in P. falciparum. Infect Genet Evol 7: 52-59.
65. Paguio, M.F., Cabrera, M., and Roepe, P.D. (2009) Chloroquine transport in Plasmodium falciparum. 2. Analysis of PfCRT-mediated drug transport using proteoliposomes and a fluorescent chloroquine probe. Biochemistry 48: 9482-9491.
66. Peel, S.A., Bright, P., Yount, B., Handy, J., and Baric, R.S. (1994) A strong association between mefloquine and halofantrine resistance and amplification, overexpression, and mutation in the P-glycoprotein gene homolog (pfmdr) of Plasmodium falciparum in vitro. Am J Trop Med Hyg 51: 648-658.
67. Peters, W., Ekong, R., Robinson, B.L., Warhurst, D.C., and Pan, X.Q. (1989) Antihistaminic drugs that reverse chloroquine resistance in Plasmodium falciparum. Lancet 2: 334-335.
68. Peters, W., Ekong, R., Robinson, B.L., Warhurst, D.C., and Pan, X.Q. (1990) The chemotherapy of rodent malaria. XLV. Reversal of chloroquine resistance in rodent and human Plasmodium by antihistaminic agents. Ann Trop Med Parasitol 84: 541-551.
69. Pleeter, P., Lekostaj, J.K., and Roepe, P.D. (2010) Purified Plasmodium falciparum multi-drug resistance protein (PfMDR 1) binds a high affinity chloroquine analogue. Mol Biochem Parasitol 173: 158-161.
70. Plowe, C.V. (2003) Monitoring antimalarial drug resistance: making the most of the tools at hand. J Exp Biol 206: 3745-3752.
71. Pradines, B., Pages, J.M., and Barbe, J. (2005) Chemosensitizers in drug transport mechanisms involved in protozoan resistance. Curr Drug Targets Infect Disord 5: 411-431.
72. Preechapornkul, P., Imwong, M., Chotivanich, K., Pongtavornpinyo, W., Dondorp, A.M., Day, N.P., et al. (2009) Plasmodium falciparum pfmdr1 amplification, mefloquine resistance, and parasite fitness. Antimicrob Agents Chemother 53: 1509-1515.
73. Price, R.N., Uhlemann, A.C., Brockman, A., McGready, R., Ashley, E., Phaipun, L., et al. (2004) Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364: 438-447.
74. Rason, M.A., Andrianantenaina, H.B., Ariey, F., Raveloson, A., Domarle, O., and Randrianarivelojosia, M. (2007) Prevalent pfmdr1 n86y mutant Plasmodium falciparum in Madagascar despite absence of pfcrt mutant strains. Am J Trop Med Hyg 76: 1079-1083.
75. Reed, M.B., Saliba, K.J., Caruana, S.R., Kirk, K., and Cowman, A.F. (2000) Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403: 906-909.
76. Roepe, P.D., and Martiney, J.A. (1999) Are ion-exchange processes central to understanding drug-resistance phenomena? Trends Pharmacol Sci 20: 62-65.
77. Rogan, A.M., Hamilton, T.C., Young, R.C., Klecker, R.W., Jr, and Ozols, R.F. (1984) Reversal of adriamycin resistance by verapamil in human ovarian cancer. Science 224: 994-996.
78. Rohrbach, P., Sanchez, C.P., Hayton, K., Friedrich, O., Patel, J., Sidhu, A.B., et al. (2006) Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. EMBO J 25: 3000-3011.
79. Sa, J.M., Twu, O., Hayton, K., Reyes, S., Fay, M.P., Ringwald, P., and Wellems, T.E. (2009) Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proc Natl Acad Sci USA 106: 18883-18889.
80. Sanchez, C.P., Stein, W., and Lanzer, M. (2003) Trans stimulation provides evidence for a drug efflux carrier as the mechanism of chloroquine resistance in Plasmodium falciparum. Biochemistry 42: 9383-9394.
81. Sanchez, C.P., McLean, J.E., Stein, W., and Lanzer, M. (2004) Evidence for a substrate specific and inhibitable drug efflux system in chloroquine resistant Plasmodium falciparum strains. Biochemistry 43: 16365-16373.
82. Sanchez, C.P., McLean, J.E., Rohrbach, P., Fidock, D.A., Stein, W.D., and Lanzer, M. (2005) Evidence for a pfcrt-associated chloroquine efflux system in the human malarial parasite Plasmodium falciparum. Biochemistry 44: 9862-9870.
83. Sanchez, C.P., Rotmann, A., Stein, W.D., and Lanzer, M. (2008) Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum. Mol Microbiol 70: 786-798.
84. Sen, S., and Ferdig, M. (2004) QTL analysis for discovery of genes involved in drug responses. Curr Drug Targets Infect Disord 4: 53-63.
85. Shen, D.W., Fojo, A., Chin, J.E., Roninson, I.B., Richert, N., Pastan, I., and Gottesman, M.M. (1986) Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science 232: 643-645.
86. Sidhu, A.B., Verdier-Pinard, D., and Fidock, D.A. (2002) Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298: 210-213.
87. Sidhu, A.B., Valderramos, S.G., and Fidock, D.A. (2005) pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Mol Microbiol 57: 913-926.
88. Sidhu, A.B., Uhlemann, A.C., Valderramos, S.G., Valderramos, J.C., Krishna, S., and Fidock, D.A. (2006) Decreasing pfmdr1 copy number in plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis 194: 528-535.
89. Sidhu, A.B., Sun, Q., Nkrumah, L.J., Dunne, M.W., Sacchettini, J.C., and Fidock, D.A. (2007) In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin. J Biol Chem 282: 2494-2504.
90. Su, X., Kirkman, L.A., Fujioka, H., and Wellems, T.E. (1997) Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa. Cell 91: 593-603.
91. Su, X., Ferdig, M.T., Huang, Y., Huynh, C.Q., Liu, A., You, J., et al. (1999) A genetic map and recombination parameters of the human malaria parasite Plasmodium falciparum. Science 286: 1351-1353.
92. Tsuruo, T., Iida, H., Tsukagoshi, S., and Sakurai, Y. (1982) Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res 42: 4730-4733.
93. Uhlemann, A.C., Ramharter, M., Lell, B., Kremsner, P.G., and Krishna, S. (2005) Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon. J Infect Dis 192: 1830-1835.
94. Uhlemann, A.C., McGready, R., Ashley, E.A., Brockman, A., Singhasivanon, P., Krishna, S., et al. (2007) Intrahost selection of Plasmodium falciparum pfmdr1 alleles after antimalarial treatment on the northwestern border of Thailand. J Infect Dis 195: 134-141.
95. Ursos, L.M., Dzekunov, S.M., and Roepe, P.D. (2000) The effects of chloroquine and verapamil on digestive vacuolar pH of P. falciparum either sensitive or resistant to chloroquine. Mol Biochem Parasitol 110: 125-134.
96. Valderramos, S.G., Valderramos, J.C., Musset, L., Purcell, L.A., Mercereau-Puijalon, O., Legrand, E., and Fidock, D.A. (2010) Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum. PLoS Pathog 6: e1000887.
97. Vieira, P.P., Ferreira, M.U., Alecrim, M.G., Alecrim, W.D., Silva, L.H., Sihuincha, M.M., et al. (2004) pfcrt polymorphism and the spread of chloroquine resistance in Plasmodium falciparum populations across the Amazon Basin. J Infect Dis 190: 417-424.
98. Wellems, T.E. (2004) Transporter of a malaria catastrophe. Nat Med 10: 1169-1171.
99. Wellems, T.E., and Plowe, C.V. (2001) Chloroquine-resistant malaria. J Infect Dis 184: 770-776.
100. Wellems, T.E., Panton, L.J., Gluzman, I.Y., Rosario, V.E., Gwadz, R.W., Walker-Jonah, A., and Krogstad, D.J. (1990) Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345: 253-255.
101. Wellems, T.E., Walker-Jonah, A., and Panton, L.J. (1991) Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc Natl Acad Sci USA 88: 3382-3386.
102. Wilson, C.M., Serrano, A.E., Wasley, A., Bogenschutz, M.P., Shankar, A.H., and Wirth, D.F. (1989) Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 244: 1184-1186.
103. Wootton, J.C., Feng, X., Ferdig, M.T., Cooper, R.A., Mu, J., Baruch, D.I., et al. (2002) Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418: 320-323.
104. Yayon, A., Cabantchik, Z.I., and Ginsburg, H. (1984) Identification of the acidic compartment of Plasmodium falciparum-infected human erythrocytes as the target of the antimalarial drug chloroquine. EMBO J 3: 2695-2700.
105. Zhang, H., Paguio, M., and Roepe, P.D. (2004) The antimalarial drug resistance protein Plasmodium falciparum chloroquine resistance transporter binds chloroquine. Biochemistry 43: 8290-8296.