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Malaria Research and Treatment
Volume 2014 (2014), Article ID 950424, 17 pages
http://dx.doi.org/10.1155/2014/950424
Review Article

Role of Different Pfcrt and Pfmdr-1 Mutations in Conferring Resistance to Antimalaria Drugs in Plasmodium falciparum

Zaid O. Ibraheem,1 R. Abd Majid,2 S. Mohd. Noor,3 H. Mohd. Sedik,4 and R. Basir1

1Pharmacology Unit, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
2Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
3Department of Hematology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
4School of Bioscience and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), 43600 Bangi, Selangor, Malaysia

Received 29 June 2014; Accepted 30 August 2014; Published 11 November 2014

Academic Editor: Polrat Wilairatana

Copyright © 2014 Zaid O. Ibraheem et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. F. Boni, D. L. Smith, and R. Laxminarayan, “Benefits of using multiple first-line therapies against malaria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 37, pp. 14216–14221, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. J. N. Burrows, D. Leroy, J. Lotharius, and D. Waterson, “Challenges in antimalarial drug discovery,” Future Medicinal Chemistry, vol. 3, no. 11, pp. 1401–1412, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. J. C. Wootton, X. Feng, M. T. Ferdig et al., “Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum,” Nature, vol. 418, no. 6895, pp. 320–323, 2002. View at Publisher · View at Google Scholar · View at Scopus
  4. C. W. Chan, R. Spathis, D. M. Reiff, S. E. McGrath, R. M. Garruto, and J. K. Lum, “Diversity of Plasmodium falciparum chloroquine resistance transporter (pfcrt) exon 2 haplotypes in the pacific from 1959 to 1979,” PLoS ONE, vol. 7, no. 1, Article ID e30213, 2012. View at Publisher · View at Google Scholar · View at Scopus
  5. S. V. Looareesuwan, C. Webster, H. K. Kyle et al., “Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand,” The American Journal of Tropical Medicine and Hygiene, vol. 54, no. 1, pp. 62–66, 1996. View at Google Scholar · View at Scopus
  6. X. C. Ding, D. Ubben, and T. N. Wells, “A framework for assessing the risk of resistance for anti-malarials in development,” Malaria Journal, vol. 11, article 292, 2012. View at Publisher · View at Google Scholar · View at Scopus
  7. T. J. C. Anderson, S. Nair, H. Qin et al., “Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?” Antimicrobial Agents and Chemotherapy, vol. 49, no. 6, pp. 2180–2188, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. M. Korsinczky, N. Chen, B. Kotecka, A. Saul, K. Rieckmann, and Q. Cheng, “Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 8, pp. 2100–2108, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. J. M. Peters, N. Chen, M. Gatton et al., “Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum,” Antimicrobial Agents and Chemotherapy, vol. 46, no. 8, pp. 2435–2441, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. P. Garner and P. M. Graves, “The benefits of artemisinin combination therapy for malaria extend beyond the individual patient,” PLoS Medicine, vol. 2, article e105, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. G. D. Shanks, “Treatment of falciparum malaria in the age of drug resistance,” Journal of Postgraduate Medicine, vol. 52, no. 4, pp. 277–280, 2006. View at Google Scholar · View at Scopus
  12. G. Santos and N. V. Torres, “New targets for drug discovery against Malaria,” PLoS ONE, vol. 8, no. 3, Article ID e59968, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. M. T. Tse, “Antimalarial drugs: a treasure trove of potential antimalarials,” Nature Reviews Drug Discovery, vol. 9, no. 7, pp. 516–517, 2010. View at Publisher · View at Google Scholar · View at Scopus
  14. D. M. Molina, R. Jafari, M. Ignatushchenko et al., “Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay,” Science, vol. 341, no. 6141, pp. 84–87, 2013. View at Publisher · View at Google Scholar · View at Scopus
  15. P. D. Dobson, K. Lanthaler, S. G. Oliver, and D. B. Kell, “Implications of the dominant role of transporters in drug uptake by cells,” Current Topics in Medicinal Chemistry, vol. 9, no. 2, pp. 163–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. A. D. Djimdé, O. K. Doumbo, J. F. Cortese et al., “A molecular marker for chloroquine-resistant falciparum malaria,” The New England Journal of Medicine, vol. 344, no. 4, pp. 257–263, 2001. View at Publisher · View at Google Scholar · View at Scopus
  17. K. L. Waller, R. A. Muhle, L. M. Ursos et al., “Chloroquine resistance modulated in vitro by expression levels of the Plasmodium falciparum chloroquine resistance transporter,” Journal of Biological Chemistry, vol. 278, no. 35, pp. 33593–33601, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. W. M. Atroosh, H. M. Al-Mekhlafi, M. A. K. Mahdy, and J. Surin, “The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia,” Malaria Journal, vol. 11, article 251, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. G. Dorsey, M. R. Kamya, A. Singh, and P. J. Rosenthal, “Polymorphisms in the Plasmodium falciparum pfcrt and pfmdr-1 genes and clinical response to chloroquine in Kampala, Uganda,” Journal of Infectious Diseases, vol. 183, no. 9, pp. 1417–1420, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. M. T. Duraisingh and A. F. Cowman, “Contribution of the pfmdr1 gene to antimalarial drug-resistance,” Acta Tropica, vol. 94, no. 3, pp. 181–190, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. R. N. Price, A.-C. Uhlemann, A. Brockman et al., “Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number,” The Lancet, vol. 364, no. 9432, pp. 438–447, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. K. Rungsihirunrat, W. Chaijareonkul, A. Seugorn, K. Na-Bangchang, and S. Thaithong, “Association between chloroquine resistance phenotypes and point mutations in pfcrt and pfmdr1 in Plasmodium falciparum isolates from Thailand,” Acta Tropica, vol. 109, no. 1, pp. 37–40, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. V. Andriantsoanirina, A. Ratsimbasoa, C. Bouchier et al., “Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in madagascar,” PLoS ONE, vol. 5, no. 10, Article ID e13281, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Van Helvoort, A. J. Smith, H. Sprong et al., “MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine,” Cell, vol. 87, no. 3, pp. 507–517, 1996. View at Publisher · View at Google Scholar · View at Scopus
  25. C. P. Sanchez, A. Rotmann, W. D. Stein, and M. Lanzer, “Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum,” Molecular Microbiology, vol. 70, no. 4, pp. 786–798, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Rohrbach, C. P. Sanchez, K. Hayton et al., “Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum,” The EMBO Journal, vol. 25, no. 13, pp. 3000–3011, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. L. von Seidlein, M. T. Duraisingh, C. J. Drakeley, R. Bailey, B. M. Greenwood, and M. Pinder, “Polymorphism of the Pfmdr1 gene and chloroquine resistance in Plasmodium falciparum in The Gambia,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 91, no. 4, pp. 450–453, 1997. View at Publisher · View at Google Scholar · View at Scopus
  28. C. M. Wilson, A. E. Serrano, A. Wasley, M. P. Bogenschutz, A. H. Shankar, and D. F. Wirth, “Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum,” Science, vol. 244, no. 4909, pp. 1184–1186, 1989. View at Publisher · View at Google Scholar · View at Scopus
  29. D. K. Raj, J. Mu, H. Jiang et al., “Disruption of a Plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione,” Journal of Biological Chemistry, vol. 284, no. 12, pp. 7687–7696, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Rosenberg, I. Litus, N. Schwarzfuchs et al., “pfmdr2 confers heavy metal resistance to Plasmodium falciparum,” Journal of Biological Chemistry, vol. 281, no. 37, pp. 27039–27045, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. J. P. Rubio and A. F. Cowman, “Plasmodium faciparum: the pfmdr2 protein is not overexpressed in chloroquine-resistant isolates of the malaria parasite,” Experimental Parasitology, vol. 79, no. 2, pp. 137–147, 1994. View at Publisher · View at Google Scholar · View at Scopus
  32. S. Briolant, M. Henry, C. Oeuvray et al., “Absence of association between piperaquine in vitro responses and polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe genes in Plasmodium falciparum,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 9, pp. 3537–3544, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. M. M. Póvoa, I. S. Adagu, S. G. Oliveira, R. L. D. Machado, M. A. Miles, and D. C. Warhurst, “Pfmdr1 (Asn)1042(ASp) and (Asp)1246(Tyr) polymorphisms, thought to be associated with chloroquine resistance, are present in chloroquine-resistant and -sensitive Brazilian field isolates of Plasmodium falciparum,” Experimental Parasitology, vol. 88, no. 1, pp. 64–68, 1998. View at Publisher · View at Google Scholar · View at Scopus
  34. M. T. Duraisingh, C. J. Drakeley, O. Muller et al., “Evidence for selection for the tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum by chloroquine and amodiaquine,” Parasitology, vol. 114, no. 3, pp. 205–211, 1997. View at Publisher · View at Google Scholar · View at Scopus
  35. H. Tinto, L. Guekoun, I. Zongo, R. T. Guiguemdé, U. D'Alessandro, and J. B. Ouédraogo, “Chloroquine-resistance molecular markers (Pfcrt T76 and Pfmdr-1 Y86) and amodiaquine resistance in Burkina Faso,” Tropical Medicine and International Health, vol. 13, no. 2, pp. 238–240, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. G. C. Barrett, Chemistry and Biochemistry of the Amino Acids, Springer, Amsterdam, The Netherlands, 1985.
  37. P. G. Bray, S. R. Hawley, M. Mungthin, and S. A. Ward, “Physicochemical properties correlated with drug resistance and the reversal of drug resistance in Plasmodium falciparum,” Molecular Pharmacology, vol. 50, no. 6, pp. 1559–1566, 1996. View at Google Scholar · View at Scopus
  38. H. A. Babiker, S. J. Pringle, A. Abdel-Muhsin, M. Mackinnon, P. Hunt, and D. Walliker, “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,” Journal of Infectious Diseases, vol. 183, no. 10, pp. 1535–1538, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. K. Haruki, P. G. Bray, S. A. Ward, M. Hommel, and G. Y. Ritchie, “Chloroquine resistance of Plasmodium falciparum: further evidence for a lack of association with mutations of the pfmdr1 gene,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 88, no. 6, p. 694, 1994. View at Publisher · View at Google Scholar · View at Scopus
  40. T. E. Wellems, L. J. Panton, I. Y. Gluzman et al., “Chloroquine resistance not linked to mdr-like genes in Plasmodium falciparum cross,” Nature, vol. 345, no. 6272, pp. 253–255, 1990. View at Publisher · View at Google Scholar · View at Scopus
  41. L. K. Basco, J. L. Bras, Z. Rhoades, and C. M. Wilson, “Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from Subsaharan Africa,” Molecular and Biochemical Parasitology, vol. 74, no. 2, pp. 157–166, 1995. View at Publisher · View at Google Scholar · View at Scopus
  42. S. J. Foote, D. E. Kyle, R. K. Martin et al., “Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum,” Nature, vol. 345, no. 6272, pp. 255–258, 1990. View at Publisher · View at Google Scholar · View at Scopus
  43. L. K. Basco and P. Ringwald, “Molecular epidemiology of malaria in Yaounde, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr 1) gene of Plasmodium falciparum,” The American Journal of Tropical Medicine and Hygiene, vol. 59, no. 4, pp. 577–581, 1998. View at Google Scholar · View at Scopus
  44. K. R. G. McCutcheon, J. A. Freese, J. A. Frean, B. L. Sharp, and M. B. Markus, “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,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 93, no. 3, pp. 300–302, 1999. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Mungthin, S. Intanakom, N. Suwandittakul et al., “Distribution of pfmdr1 polymorphisms in Plasmodium falciparum isolated from Southern Thailand,” Malaria Journal, vol. 13, no. 1, article 117, 2014. View at Publisher · View at Google Scholar · View at Scopus
  46. M. B. Reed, K. J. Saliba, S. R. Caruana, K. Kirk, and A. F. Cowman, “Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum,” Nature, vol. 403, no. 6772, pp. 906–909, 2000. View at Publisher · View at Google Scholar · View at Scopus
  47. C. E. Griffin, J. M. Hoke, U. Samarakoon et al., “Mutation in the Plasmodium falciparum CRT protein determines the stereospecific activity of antimalarial Cinchona alkaloids,” Antimicrobial Agents and Chemotherapy, vol. 56, no. 10, pp. 5356–5364, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. M. B. Reed, K. J. Saliba, S. R. Caruana, K. Kirk, and A. F. Cowman, “Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum,” Nature, vol. 403, no. 6772, pp. 906–909, 2000. View at Publisher · View at Google Scholar · View at Scopus
  49. G. Y. Ritchie, M. Mungthin, J. E. Green, P. G. Bray, S. R. Hawley, and S. A. Ward, “In vitro selection of halofantrine resistance in Plasmodium falciparum is not associated with increased expression of Pgh1,” Molecular and Biochemical Parasitology, vol. 83, no. 1, pp. 35–46, 1996. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Chavchich, L. Gerena, J. Peters, N. Chen, Q. Cheng, and D. E. Kyle, “Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 6, pp. 2455–2464, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. J. Mu, M. T. Ferdig, X. Feng et al., “Multiple transporters associated with malaria parasite responses to chloroquine and quinine,” Molecular Microbiology, vol. 49, no. 4, pp. 977–989, 2003. View at Publisher · View at Google Scholar · View at Scopus
  52. H. Zhang, E. M. Howard, and P. D. Roepe, “Analysis of the antimalarial drug resistance protein Pfcrt expressed in yeast,” Journal of Biological Chemistry, vol. 277, no. 51, pp. 49767–49775, 2002. View at Publisher · View at Google Scholar · View at Scopus
  53. A. B. Singh Sidhu, D. Verdier-Pinard, and D. A. Fidock, “Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations,” Science, vol. 298, no. 5591, pp. 210–213, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. S. G. Valderramos, J. C. Valderramos, L. Musset et al., “Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum,” PLoS pathogens, vol. 6, no. 5, Article ID e1000887, 2010. View at Google Scholar · View at Scopus
  55. G. Awasthi and A. Das, “Genetics of chloroquine-resistant malaria: a haplotypic view,” Memórias do Instituto Oswaldo Cruz, vol. 108, no. 8, pp. 947–961, 2013. View at Publisher · View at Google Scholar · View at Scopus
  56. V. S. M. A. D. Kolippakkam, “Amino acid physicochemical properties database,” Bioinformation, vol. 1, no. 1, pp. 2–4, 2005. View at Google Scholar
  57. J. Antosiewicz, J. A. McCammon, and M. K. Gilson, “Prediction of pH-dependent properties of proteins,” Journal of Molecular Biology, vol. 238, no. 3, pp. 415–436, 1994. View at Publisher · View at Google Scholar · View at Scopus
  58. N. Chen, D. E. Kyle, C. Pasay et al., “Pfcrt allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum isolates from the Philippines,” Antimicrobial Agents and Chemotherapy, vol. 47, no. 11, pp. 3500–3505, 2003. View at Publisher · View at Google Scholar · View at Scopus
  59. V. Lakshmanan, P. G. Bray, D. Verdier-Pinard et al., “A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance,” EMBO Journal, vol. 24, no. 13, pp. 2294–2305, 2005. View at Publisher · View at Google Scholar · View at Scopus
  60. R. A. H. Umar, S. W. Hassan, M. J. Ladan, M. Nma Jiya, M. K. Abubakar, and U. Nata'ala, “The association of K76T mutation in Pfcrt gene and chloroquine treatment failure in uncomplicated Plasmodium falciparum malaria in a cohort of Nigerian children,” Journal of Applied Sciences, vol. 7, no. 23, pp. 3696–3704, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. S. G. Evans and I. Havlik, “In vitro drug interaction between amantadine and classical antimalarial drugs in Plasmodium falciparum infections,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 88, no. 6, pp. 683–686, 1994. View at Publisher · View at Google Scholar · View at Scopus
  62. R. A. Cooper, M. T. Ferdig, X.-Z. Su et al., “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,” Molecular Pharmacology, vol. 61, no. 1, pp. 35–42, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. R. A. Bayoumi, H. A. Babiker, S. M. Ibrahim et al., “Chloroquine-resistant Plasmodium falciparum in Eastern Sudan,” Acta Tropica, vol. 46, no. 3, pp. 157–165, 1989. View at Publisher · View at Google Scholar · View at Scopus
  64. M. A. Travassos and M. K. Laufer, “Resistance to antimalarial drugs: molecular, pharmacologic, and clinical considerations,” Pediatric Research, vol. 65, no. 5, article 2, pp. 64R–70R, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. J. Keen, G. A. Farcas, K. Zhong, S. Yohanna, M. W. Dunne, and K. C. Kain, “Real-time PCR assay for rapid detection and analysis of PfCRT haplotypes of chloroquine-resistant Plasmodium falciparum isolates from India,” Journal of Clinical Microbiology, vol. 45, no. 9, pp. 2889–2893, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. G. Awasthi, G. B. K. Satya, and A. Das, “Pfcrt haplotypes and the evolutionary history of chloroquine-resistant Plasmodium falciparum,” Memórias do Instituto Oswaldo Cruz, vol. 107, no. 1, pp. 129–134, 2012. View at Publisher · View at Google Scholar · View at Scopus
  67. R. K. Mehlotra, H. Fujioka, P. D. Roepe et al., “Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 22, pp. 12689–12694, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. S. G. Valderramos and D. A. Fidock, “Transporters involved in resistance to antimalarial drugs,” Trends in Pharmacological Sciences, vol. 27, no. 11, pp. 594–601, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. P. P. Vieira, M. U. Ferreira, M. D. G. Alecrim et al., “pfcrt polymorphism and the spread of chloroquine resistance in Plasmodium falciparum populations across the Amazon Basin,” Journal of Infectious Diseases, vol. 190, no. 2, pp. 417–424, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. T. N. Bennett, A. D. Kosar, L. M. B. Ursos et al., “Drug resistance-associated pfCRT mutations confer decreased Plasmodium falciparum digestive vacuolar pH,” Molecular and Biochemical Parasitology, vol. 133, no. 1, pp. 99–114, 2004. View at Publisher · View at Google Scholar · View at Scopus
  71. A. B. S. Sidhu, D. Verdier-Pinard, and D. A. Fidock, “Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations,” Science, vol. 298, no. 5591, pp. 210–213, 2002. View at Publisher · View at Google Scholar · View at Scopus
  72. H. Jiang, N. Li, V. Gopalan et al., “High recombination rates and hotspots in a Plasmodium falciparum genetic cross,” Genome Biology, vol. 12, no. 4, article R33, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. T. Mita, A. Kaneko, F. Hombhanje et al., “Role of pfmdr1 mutations on chloroquine resistance in Plasmodium falciparum isolates with pfcrt K76T from Papua New Guinea,” Acta Tropica, vol. 98, no. 2, pp. 137–144, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Papakrivos, J. M. Sá, and T. E. Wellems, “Functional characterization of the Plasmodium falciparum chloroquine-resistance transporter (PfCRT) in transformed Dictyostelium discoideum vesicles,” PLoS ONE, vol. 7, no. 6, Article ID e39569, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. K. J. Saliba and K. Kirki, “pH regulation in the intracellular malaria parasite, Plasmodium falciparum. H+ extrusion via a V-type H+-ATPase,” The Journal of Biological Chemistry, vol. 274, no. 47, pp. 33213–33219, 1999. View at Publisher · View at Google Scholar · View at Scopus
  76. K. J. Saliba, R. J. W. Allen, S. Zissis, P. G. Bray, S. A. Ward, and K. Kirk, “Acidification of the malaria parasite's digestive vacuole by a H+-ATPase and a H+-pyrophosphatase,” Journal of Biological Chemistry, vol. 278, no. 8, pp. 5605–5612, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. A. M. Lehane and K. Kirk, “Chloroquine resistance-conferring mutations in pfcrt give rise to a chloroquine-associated H+ leak from the malaria parasite's digestive vacuole,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 12, pp. 4374–4380, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. A. M. Lehane, R. Hayward, K. J. Saliba, and K. Kirk, “A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites,” Journal of Cell Science, vol. 121, no. 10, pp. 1624–1632, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. M. Henry, S. Alibert, E. Orlandi-Pradines et al., “Chloroquine resistance reversal agents as promising antimalarial drugs,” Current Drug Targets, vol. 7, no. 8, pp. 935–948, 2006. View at Publisher · View at Google Scholar · View at Scopus
  80. D. C. Warhurst, “Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine,” Malaria Journal, vol. 2, article 31, 2003. View at Google Scholar · View at Scopus
  81. O. K. Amodu, D. L. Hartl, and S. W. Roy, “Patterns of polymorphism in genomic regions flanking three highly polymorphic surface antigens in Plasmodium falciparum,” Molecular and Biochemical Parasitology, vol. 159, no. 1, pp. 1–6, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. S. G. Evans and I. Havlik, “Plasmodium falciparum: effects of amantadine, an antiviral, on chloroquine-resistant and -sensitive parasites in vitro and its influence on chloroquine activity,” Biochemical Pharmacology, vol. 45, no. 5, pp. 1168–1170, 1993. View at Publisher · View at Google Scholar · View at Scopus
  83. S. I. Hay, C. A. Guerra, A. J. Tatem, A. M. Noor, and R. W. Snow, “The global distribution and population at risk of malaria: past, present, and future,” Lancet Infectious Diseases, vol. 4, no. 6, pp. 327–336, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. M. L. Kelly, J. A. Cook, P. Brown-Augsburger, B. A. Heinz, M. C. Smith, and L. H. Pinto, “Demonstrating the intrinsic ion channel activity of virally encoded proteins,” FEBS Letters, vol. 552, no. 1, pp. 61–67, 2003. View at Publisher · View at Google Scholar · View at Scopus
  85. J. Le Bras and R. Durand, “The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum,” Fundamental and Clinical Pharmacology, vol. 17, no. 2, pp. 147–153, 2003. View at Publisher · View at Google Scholar · View at Scopus
  86. P. G. Bray and S. A. Ward, “A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum,” Pharmacology and Therapeutics, vol. 77, no. 1, pp. 1–28, 1998. View at Publisher · View at Google Scholar · View at Scopus
  87. D. J. Johnson, D. A. Fidock, M. Mungthin et al., “Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents,” Molecular Cell, vol. 15, no. 6, pp. 867–877, 2004. View at Publisher · View at Google Scholar · View at Scopus
  88. J. Wooden, E. E. Gould, A. T. Paull, and C. H. Sibley, “Plasmodium falciparum: a simple polymerase chain reaction method for differentiating strains,” Experimental Parasitology, vol. 75, no. 2, pp. 207–212, 1992. View at Publisher · View at Google Scholar · View at Scopus
  89. P. G. Bray, O. Janneh, K. J. Raynes, M. Mungthin, H. Ginsburg, and S. A. Ward, “Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum,” Journal of Cell Biology, vol. 145, no. 2, pp. 363–376, 2000. View at Publisher · View at Google Scholar · View at Scopus
  90. S. A. Peel, S. C. Merritt, J. Handy, and R. S. Baric, “Derivation of highly mefloquine-resistant lines from Plasmodium falciparum in vitro,” American Journal of Tropical Medicine and Hygiene, vol. 48, no. 3, pp. 385–397, 1993. View at Google Scholar · View at Scopus
  91. S. A. Peel, P. Bright, B. Yount, J. Handy, and R. S. Baric, “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,” The American Journal of Tropical Medicine and Hygiene, vol. 51, no. 5, pp. 648–658, 1994. View at Google Scholar · View at Scopus
  92. P. Lim, S. Chy, F. Ariey et al., “pfcrt polymorphism and chloroquine resistance in Plasmodium falciparum strains isolated in Cambodia,” Antimicrobial Agents and Chemotherapy, vol. 47, no. 1, pp. 87–94, 2003. View at Publisher · View at Google Scholar · View at Scopus
  93. G. Lefèvre, S. Looareesuwan, S. Treeprasertsuk et al., “A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand,” The American Journal of Tropical Medicine and Hygiene, vol. 64, no. 5, pp. 247–256, 2001. View at Google Scholar · View at Scopus
  94. M. Nateghpour, S. A. Ward, and R. E. Howells, “Development of halofantrine resistance and determination of cross- resistance patterns in Plasmodium falciparum,” Antimicrobial Agents and Chemotherapy, vol. 37, no. 11, pp. 2337–2343, 1993. View at Publisher · View at Google Scholar · View at Scopus
  95. L. Mwai, S. M. Kiara, A. Abdirahman et al., “In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 12, pp. 5069–5073, 2009. View at Publisher · View at Google Scholar · View at Scopus
  96. L. Mwai, A. Diriye, V. Masseno et al., “Genome wide adaptations of Plasmodium falciparum in response to Lumefantrine selective drug pressure,” PLoS ONE, vol. 7, no. 2, Article ID e31623, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. V. Andriantsoanirina, A. Ratsimbasoa, C. Bouchier et al., “Plasmodium falciparum drug resistance in Madagascar: facing the spread of unusual pfdhfr and pfmdr-1 haplotypes and the decrease of dihydroartemisinin susceptibility,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 11, pp. 4588–4597, 2009. View at Publisher · View at Google Scholar · View at Scopus
  98. C. E. Griffin, J. M. Hoke, U. Samarakoon et al., “Mutation in the Plasmodium falciparum CRT protein determines the stereospecific activity of antimalarial Cinchona alkaloids,” Antimicrobial Agents and Chemotherapy, vol. 56, no. 10, pp. 5356–5364, 2012. View at Publisher · View at Google Scholar · View at Scopus
  99. J. M. Sá, O. Twu, K. Hayton et al., “Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 45, pp. 18883–18889, 2009. View at Publisher · View at Google Scholar · View at Scopus