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Antimicrobial Drug Resistance pp 629–647Cite as

Mechanisms of Antimalarial Drug Resistance

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Abstract

It has been estimated that in 2013 there were approximately 198 million cases of malaria (with an uncertainty range of 124–283 million) and an estimated 584,000 deaths (with an uncertainty range of 367,000–755,000), with the majority of deaths amongst African children under 5 years of age [1]. As a result of global efforts, including in transmission control (e.g. removal of breeding sites using insecticides and prevention of human contact through screens and bed nets), improved antimalarial chemotherapy and early effective case management, malaria mortality rates have fallen by 47 % globally and by 54 % in Africa since 2000 [1].

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References

  1. WHO. World Malaria Report 2014. World Health Organisation; 2014.

    Google Scholar 

  2. Snow RW, Trape JF, Marsh K. The past, present and future of childhood malaria mortality in Africa. Trends Parasitol. 2001;17(12):593–7.

    Article  CAS  PubMed  Google Scholar 

  3. Wongsrichanalai C, et al. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002;2(4):209–18.

    Article  CAS  PubMed  Google Scholar 

  4. Wootton JC, et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature. 2002;418(6895):320–3.

    Article  CAS  PubMed  Google Scholar 

  5. Chen N, et al. pfcrt Allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum isolates from the Philippines. Antimicrob Agents Chemother. 2003;47(11):3500–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. White NJ. Antimalarial drug resistance: the pace quickens. J Antimicrob Chemother. 1992;30(5):571–85.

    Article  CAS  PubMed  Google Scholar 

  7. Sibley CH, et al. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol. 2001;17(12):582–8.

    Article  CAS  PubMed  Google Scholar 

  8. Glew RH, et al. Multidrug-resistant strain of Plasmodium falciparum from eastern Colombia. J Infect Dis. 1974;129(4):385–90.

    Article  CAS  PubMed  Google Scholar 

  9. Hall AP, et al. Amodiaquine resistant falciparum malaria in Thailand. Am J Trop Med Hyg. 1975;24(4):575–80.

    Article  CAS  PubMed  Google Scholar 

  10. Campbell CC, et al. Evaluation of amodiaquine treatment of chloroquine-resistant Plasmodium falciparum malaria on Zanzibar, 1982. Am J Trop Med Hyg. 1983;32(6):1216–20.

    Article  CAS  PubMed  Google Scholar 

  11. Childs GE, et al. A comparison of the in vitro activities of amodiaquine and desethylamodiaquine against isolates of Plasmodium falciparum. Am J Trop Med Hyg. 1989;40(1):7–11.

    Article  CAS  PubMed  Google Scholar 

  12. WHO. Global report on antimalarial drug efficacy and drug resistance: 2000–2010. 2010.

    Google Scholar 

  13. Sa JM, et al. Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proc Natl Acad Sci U S A. 2009;106(45):18883–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fontanet AL, et al. High prevalence of mefloquine-resistant falciparum malaria in eastern Thailand. Bull World Health Organ. 1993;71(3–4):377–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Noedl H, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008;359(24):2619–20.

    Article  CAS  PubMed  Google Scholar 

  16. Dondorp AM, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361(5):455–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. WHO. Status report on artemisinin resistance. 2014.

    Google Scholar 

  18. Perrin D. Dissociation constants of organic bases in aqueous solution. London: Butterworth; 1965.

    Google Scholar 

  19. Yayon A, Cabantchik ZI, Ginsburg H. Susceptibility of human malaria parasites to chloroquine is pH dependent. Proc Natl Acad Sci U S A. 1985;82(9):2784–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Krogstad DJ, Schlesinger PH, Gluzman IY. Antimalarials increase vesicle pH in Plasmodium falciparum. J Cell Biol. 1985;101(6):2302–9.

    Article  CAS  PubMed  Google Scholar 

  21. Bennett TN, et al. Drug resistance-associated pfCRT mutations confer decreased Plasmodium falciparum digestive vacuolar pH. Mol Biochem Parasitol. 2004;133(1):99–114.

    Article  CAS  PubMed  Google Scholar 

  22. Yayon A, Cabantchik ZI, Ginsburg H. Identification of the acidic compartment of Plasmodium falciparum-infected human erythrocytes as the target of the antimalarial drug chloroquine. EMBO J. 1984;3(11):2695–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fitch CD, Kanjananggulpan P. The state of ferriprotoporphyrin IX in malaria pigment. J Biol Chem. 1987;262(32):15552–5.

    CAS  PubMed  Google Scholar 

  24. Egan TJ, et al. Fate of haem iron in the malaria parasite Plasmodium falciparum. Biochem J. 2002;365(Pt 2):343–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Slater AF, Cerami A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites [see comments]. Nature. 1992;355(6356):167–9.

    Article  CAS  PubMed  Google Scholar 

  26. Sullivan Jr DJ, et al. On the molecular mechanism of chloroquine’s antimalarial action. Proc Natl Acad Sci U S A. 1996;93(21):11865–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bray PG, et al. Access to hematin: the basis of chloroquine resistance. Mol Pharmacol. 1998;54(1):170–9.

    CAS  PubMed  Google Scholar 

  28. Bray PG, et al. Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum. J Cell Biol. 1999;145(2):363–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Macomber PB, O’Brien RL, Hahn FE. Chloroquine: physiological basis of drug resistance in Plasmodium berghei. Science. 1966;152(727):1374–5.

    Article  CAS  PubMed  Google Scholar 

  30. Fitch CD. Plasmodium falciparum in owl monkeys: drug resistance and chloroquine binding capacity. Science. 1970;169(942):289–90.

    Article  CAS  PubMed  Google Scholar 

  31. Diribe CO, Warhurst DC. A study of the uptake of chloroquine in malaria-infected erythrocytes. High and low affinity uptake and the influence of glucose and its analogues. Biochem Pharmacol. 1985;34(17):3019–27.

    Article  CAS  PubMed  Google Scholar 

  32. Verdier F, et al. Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes during in vitro culture and its relationship to chloroquine resistance. Antimicrob Agents Chemother. 1985;27(4):561–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Geary TG, Jensen JB, Ginsburg H. Uptake of [3H]chloroquine by drug-sensitive and -resistant strains of the human malaria parasite Plasmodium falciparum. Biochem Pharmacol. 1986;35(21):3805–12.

    Article  CAS  PubMed  Google Scholar 

  34. Gluzman IY, Schlesinger PH, Krogstad DJ. Inoculum effect with chloroquine and Plasmodium falciparum. Antimicrob Agents Chemother. 1987;31(1):32–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kirk K, Saliba KJ. Chloroquine resistance and the pH of the malaria parasite’s digestive vacuole. Drug Resist Updat. 2001;4(6):335–7.

    Article  CAS  PubMed  Google Scholar 

  36. Spiller DG, et al. The pH of the Plasmodium falciparum digestive vacuole: holy grail or dead-end trail? Trends Parasitol. 2002;18(10):441–4.

    Article  CAS  PubMed  Google Scholar 

  37. Bray PG, et al. Distribution of acridine orange fluorescence in Plasmodium falciparum-infected erythrocytes and its implications for the evaluation of digestive vacuole pH. Mol Biochem Parasitol. 2002;119(2):301–4. discussion 307–9, 311–3.

    Article  CAS  PubMed  Google Scholar 

  38. Ursos LM, Dzekunov SM, Roepe PD. The effects of chloroquine and verapamil on digestive vacuolar pH of P. falciparum either sensitive or resistant to chloroquine. Mol Biochem Parasitol. 2000;110(1):125–34.

    Article  CAS  PubMed  Google Scholar 

  39. Dzekunov SM, Ursos LM, Roepe PD. Digestive vacuolar pH of intact intraerythrocytic P. falciparum either sensitive or resistant to chloroquine. Mol Biochem Parasitol. 2000;110(1):107–24.

    Article  CAS  PubMed  Google Scholar 

  40. Wissing F, et al. Illumination of the malaria parasite Plasmodium falciparum alters intracellular pH. Implications for live cell imaging. J Biol Chem. 2002;277(40):37747–55.

    Article  CAS  PubMed  Google Scholar 

  41. Ursos LM, Roepe PD. Chloroquine resistance in the malarial parasite, Plasmodium falciparum. Med Res Rev. 2002;22(5):465–91.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang J, Krugliak M, Ginsburg H. The fate of ferriprotorphyrin IX in malaria infected erythrocytes in conjunction with the mode of action of antimalarial drugs. Mol Biochem Parasitol. 1999;99(1):129–41.

    Article  CAS  PubMed  Google Scholar 

  43. Sanchez CP, Stein W, Lanzer M. Trans stimulation provides evidence for a drug efflux carrier as the mechanism of chloroquine resistance in Plasmodium falciparum. Biochemistry. 2003;42(31):9383–94.

    Article  CAS  PubMed  Google Scholar 

  44. Johnson DJ, et al. Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol Cell. 2004;15(6):867–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sanchez CP, Wunsch S, Lanzer M. Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype. J Biol Chem. 1997;272(5):2652–8.

    Article  CAS  PubMed  Google Scholar 

  46. Wellems TE, et al. Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross [see comments]. Nature. 1990;345(6272):253–5.

    Article  CAS  PubMed  Google Scholar 

  47. Wellems TE, Walker-Jonah A, Panton LJ. Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc Natl Acad Sci U S A. 1991;88(8):3382–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Walker-Jonah A, et al. An RFLP map of the Plasmodium falciparum genome, recombination rates and favored linkage groups in a genetic cross. Mol Biochem Parasitol. 1992;51(2):313–20.

    Article  CAS  PubMed  Google Scholar 

  49. Su X, et al. A genetic map and recombination parameters of the human malaria parasite plasmodium falciparum [In Process Citation]. Science. 1999;286(5443):1351–3.

    Article  CAS  PubMed  Google Scholar 

  50. Su X, et al. Complex polymorphisms in an approximately kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa. Cell. 1997;91(5):593–603.

    Article  CAS  PubMed  Google Scholar 

  51. Fidock DA, et al. Allelic modifications of the cg2 and cg1 genes do not alter the chloroquine response of drug-resistant Plasmodium falciparum. Mol Biochem Parasitol. 2000;110(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  52. Fidock DA, et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell. 2000;6(4):861–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Basco LK, Ringwald P. Analysis of the key pfcrt point mutation and in vitro and in vivo response to chloroquine in Yaounde, Cameroon. J Infect Dis. 2001;183(12):1828–31.

    Article  CAS  PubMed  Google Scholar 

  54. Chen N, et al. Sequence polymorphisms in pfcrt are strongly associated with chloroquine resistance in Plasmodium falciparum. J Infect Dis. 2001;183(10):1543–5.

    Article  CAS  PubMed  Google Scholar 

  55. Mehlotra RK, et al. 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 U S A. 2001;98(22):12689–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science. 2002;298(5591):210–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kuhn Y, et al. Trafficking of the phosphoprotein PfCRT to the digestive vacuolar membrane in Plasmodium falciparum. Traffic. 2010;11(2):236–49.

    Article  CAS  PubMed  Google Scholar 

  58. Ecker A, et al. PfCRT and its role in antimalarial drug resistance. Trends Parasitol. 2012;28(11):504–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nomura T, et al. Evidence for different mechanisms of chloroquine resistance in 2 Plasmodium species that cause human malaria. J Infect Dis. 2001;183(11):1653–61.

    Article  CAS  PubMed  Google Scholar 

  60. Picot S, et al. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malar J. 2009;8:89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Ferdig MT, et al. Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol. 2004;52(4):985–97.

    Article  CAS  PubMed  Google Scholar 

  62. Kublin JG, et al. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis. 2003;187(12):1870–5.

    Article  PubMed  Google Scholar 

  63. Wang X, et al. Decreased prevalence of the Plasmodium falciparum chloroquine resistance transporter 76T marker associated with cessation of chloroquine use against P. falciparum malaria in Hainan, People’s Republic of China. Am J Trop Med Hyg. 2005;72(4):410–4.

    CAS  PubMed  Google Scholar 

  64. Mwai L, et al. Chloroquine resistance before and after its withdrawal in Kenya. Malar J. 2009;8:106.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Zhang H, Howard EM, Roepe PD. Analysis of the antimalarial drug resistance protein Pfcrt expressed in yeast. J Biol Chem. 2002;277(51):49767–75.

    Article  CAS  PubMed  Google Scholar 

  66. Warhurst DC, Craig JC, Adagu IS. Lysosomes and drug resistance in malaria. Lancet. 2002;360(9345):1527–9.

    Article  PubMed  Google Scholar 

  67. Krogstad DJ, et al. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science. 1987;238(4831):1283–5.

    Article  CAS  PubMed  Google Scholar 

  68. Krogstad DJ, et al. Energy dependence of chloroquine accumulation and chloroquine efflux in Plasmodium falciparum. Biochem Pharmacol. 1992;43(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  69. Ward S. Drug resistance mechanisms in malaria. Pharmacologist. 2002;44:A76.

    Google Scholar 

  70. Bray PG, et al. Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. Mol Microbiol. 2005;56(2):323–33.

    Article  CAS  PubMed  Google Scholar 

  71. Nessler S, et al. Evidence for activation of endogenous transporters in Xenopus laevis oocytes expressing the Plasmodium falciparum chloroquine resistance transporter, PfCRT. J Biol Chem. 2004;279(38):39438–46.

    Article  CAS  PubMed  Google Scholar 

  72. Bray PG, et al. PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX. Mol Microbiol. 2006;62(1):238–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Martin RE, Kirk K. The malaria parasite’s chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Mol Biol Evol. 2004;21(10):1938–49.

    Article  CAS  PubMed  Google Scholar 

  74. Tran CV, Saier Jr MH. The principal chloroquine resistance protein of Plasmodium falciparum is a member of the drug/metabolite transporter superfamily. Microbiology. 2004;150(Pt 1):1–3.

    Article  CAS  PubMed  Google Scholar 

  75. Bray PG, Ward SA. A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum. Pharmacol Ther. 1998;77(1):1–28.

    Article  CAS  PubMed  Google Scholar 

  76. Martin RE, et al. Chloroquine transport via the malaria parasite’s chloroquine resistance transporter. Science. 2009;325(5948):1680–2.

    Article  CAS  PubMed  Google Scholar 

  77. Maughan SC, et al. Plant homologs of the Plasmodium falciparum chloroquine-resistance transporter, PfCRT, are required for glutathione homeostasis and stress responses. Proc Natl Acad Sci U S A. 2010;107(5):2331–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Patzewitz EM, et al. Glutathione transport: a new role for PfCRT in chloroquine resistance. Antioxid Redox Signal. 2013;19(7):683–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lehane AM, et al. Degrees of chloroquine resistance in Plasmodium - is the redox system involved? Int J Parasitol Drugs Drug Resist. 2012;2:47–57.

    Article  PubMed  CAS  Google Scholar 

  80. Wilson CM, et al. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science. 1989;244(4909):1184–6.

    Article  CAS  PubMed  Google Scholar 

  81. Zalis MG, et al. Characterization of the pfmdr2 gene for Plasmodium falciparum [published erratum appears in Mol Biochem Parasitol 1994 Feb;63(2):311]. Mol Biochem Parasitol. 1993;62(1):83–92.

    Article  CAS  PubMed  Google Scholar 

  82. Rubio JP, Cowman AF. Plasmodium falciparum: the pfmdr2 protein is not overexpressed in chloroquine-resistant isolates of the malaria parasite. Exp Parasitol. 1994;79(2):137–47.

    Article  CAS  PubMed  Google Scholar 

  83. Rubio JP, Thompson JK, Cowman AF. The var genes of Plasmodium falciparum are located in the subtelomeric region of most chromosomes. EMBO J. 1996;15(15):4069–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Foote SJ, et al. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum [see comments]. Nature. 1990;345(6272):255–8.

    Article  CAS  PubMed  Google Scholar 

  85. Wilson CM, et al. Amplification of pfmdr 1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand. Mol Biochem Parasitol. 1993;57(1):151–60.

    Article  CAS  PubMed  Google Scholar 

  86. Basco LK, et al. Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from sub-Saharan Africa. Mol Biochem Parasitol. 1995;74(2):157–66.

    Article  CAS  PubMed  Google Scholar 

  87. Basco LK, et al. Plasmodium falciparum: molecular characterization of multidrug-resistant Cambodian isolates. Exp Parasitol. 1996;82(2):97–103.

    Article  CAS  PubMed  Google Scholar 

  88. Cowman AF, et al. A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. J Cell Biol. 1991;113(5):1033–42.

    Article  CAS  PubMed  Google Scholar 

  89. Povoa MM, et al. 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. 1998;88(1):64–8.

    Article  CAS  PubMed  Google Scholar 

  90. Reed MB, et al. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature. 2000;403(6772):906–9.

    Article  CAS  PubMed  Google Scholar 

  91. Foote SJ, et al. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell. 1989;57(6):921–30.

    Article  CAS  PubMed  Google Scholar 

  92. Cowman AF, Galatis D, Thompson JK. 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 U S A. 1994;91(3):1143–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Price RN, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004;364(9432):438–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Price RN, et al. Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis. 2006;42(11):1570–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Venkatesan M, et al. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. Am J Trop Med Hyg. 2014;91(4):833–43.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Davis TM, et al. Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65(1):75–87.

    Article  CAS  PubMed  Google Scholar 

  97. Fan B, et al. In vitro sensitivity of Plasmodium falciparum to chloroquine, piperaquine, pyronaridine and artesunate in Yuxi prefecture of Yunnan province. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 1998;16(6):460–2.

    CAS  PubMed  Google Scholar 

  98. Yang H, et al. Sensitivity of Plasmodium falciparum to seven antimalarials in China-Laos border. Chung Kuo Chi Sheng Chung Hsueh Yu Chi Sheng Chung Ping Tsa Chih. 1995;13(2):111–3.

    CAS  PubMed  Google Scholar 

  99. Eastman RT, et al. Piperaquine resistance is associated with a copy number variation on chromosome 5 in drug-pressured Plasmodium falciparum parasites. Antimicrob Agents Chemother. 2011;55(8):3908–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Baraka V, et al. In vivo selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemether-lumefantrine and dihydroartemisinin-piperaquine in Burkina Faso. Antimicrob Agents Chemother. 2015;59(1):734–7.

    Article  PubMed  CAS  Google Scholar 

  101. Pascual A, et al. In vitro piperaquine susceptibility is not associated with the Plasmodium falciparum chloroquine resistance transporter gene. Malar J. 2013;12:431.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Pukrittayakamee S, et al. Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand. Trans R Soc Trop Med Hyg. 1994;88(3):324–7.

    Article  CAS  PubMed  Google Scholar 

  103. Jelinek T, et al. Quinine resistant falciparum malaria acquired in east Africa. Trop Med Parasitol. 1995;46(1):38–40.

    CAS  PubMed  Google Scholar 

  104. Segurado AA, di Santi SM, Shiroma M. In vivo and in vitro Plasmodium falciparum resistance to chloroquine, amodiaquine and quinine in the Brazilian Amazon. Rev Inst Med Trop Sao Paulo. 1997;39(2):85–90.

    Article  CAS  PubMed  Google Scholar 

  105. Cooper RA, et al. Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereo-specific quinine and quinidine responses in Plasmodium falciparum. Mol Pharmacol. 2002;61(1):35–42.

    Article  CAS  PubMed  Google Scholar 

  106. Menard D, et al. Global analysis of Plasmodium falciparum Na(+)/H(+) exchanger (pfnhe-1) allele polymorphism and its usefulness as a marker of in vitro resistance to quinine. Int J Parasitol Drugs Drug Resist. 2013;3:8–19.

    Article  PubMed  Google Scholar 

  107. Triglia T, Cowman AF. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Proc Natl Acad Sci U S A. 1994;91(15):7149–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kasekarn W, et al. Molecular characterization of bifunctional hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase from Plasmodium falciparum. Mol Biochem Parasitol. 2004;137(1):43–53.

    Article  CAS  PubMed  Google Scholar 

  109. Bzik DJ, et al. Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene. Proc Natl Acad Sci U S A. 1987;84(23):8360–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang P, et al. Transfection studies to explore essential folate metabolism and antifolate drug synergy in the human malaria parasite Plasmodium falciparum. Mol Microbiol. 2004;51(5):1425–38.

    Article  CAS  PubMed  Google Scholar 

  111. Watkins WM, et al. Chlorproguanil/dapsone for the treatment of non-severe Plasmodium falciparum malaria in Kenya: a pilot study. Trans R Soc Trop Med Hyg. 1988;82(3):398–403.

    Article  CAS  PubMed  Google Scholar 

  112. Wootton DG, et al. Open-label comparative clinical study of chlorproguanil-dapsone fixed dose combination (Lapdap) alone or with three different doses of artesunate for uncomplicated Plasmodium falciparum malaria. PLoS One. 2008;3(3):e1779.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Winstanley P. Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria. Trop Med Int Health. 2001;6(11):952–4.

    Article  CAS  PubMed  Google Scholar 

  114. Brooks DR, et al. 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. 1994;224(2):397–405.

    Article  CAS  PubMed  Google Scholar 

  115. Triglia T, et al. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A. 1997;94(25):13944–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Triglia T, et al. Allelic exchange at the endogenous genomic locus in Plasmodium falciparum proves the role of dihydropteroate synthase in sulfadoxine-resistant malaria. EMBO J. 1998;17(14):3807–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Triglia T, Cowman AF. The mechanism of resistance to sulfa drugs in Plasmodium falciparum. Drug Resist Updat. 1999;2(1):15–9.

    Article  CAS  PubMed  Google Scholar 

  118. Wang P, et al. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol Biochem Parasitol. 1997;89(2):161–77.

    Article  CAS  PubMed  Google Scholar 

  119. Wang P, et al. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Mol Microbiol. 1997;23(5):979–86.

    Article  CAS  PubMed  Google Scholar 

  120. Cowman AF, et al. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc Natl Acad Sci U S A. 1988;85(23):9109–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Peterson DS, Walliker D, Wellems TE. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci U S A. 1988;85(23):9114–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wu Y, Kirkman LA, Wellems TE. Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine. Proc Natl Acad Sci U S A. 1996;93(3):1130–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yuthavong Y. Basis for antifolate action and resistance in malaria. Microbes Infect. 2002;4(2):175–82.

    Article  CAS  PubMed  Google Scholar 

  124. Baca AM, et al. Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action. J Mol Biol. 2000;302(5):1193–212.

    Article  CAS  PubMed  Google Scholar 

  125. Sirawaraporn W, Yuthavong Y. Kinetic and molecular properties of dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi. Mol Biochem Parasitol. 1984;10(3):355–67.

    Article  CAS  PubMed  Google Scholar 

  126. Snewin VA, et al. Characterisation of the dihydrofolate reductase-thymidylate synthetase gene from human malaria parasites highly resistant to pyrimethamine. Gene. 1989;76(1):41–52.

    Article  CAS  PubMed  Google Scholar 

  127. Yuvaniyama J, et al. Insights into antifolate resistance from malarial DHFR-TS structures. Nat Struct Biol. 2003;10(5):357–65.

    Article  CAS  PubMed  Google Scholar 

  128. Kublin JG, et al. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis. 2002;185(3):380–8.

    Article  CAS  PubMed  Google Scholar 

  129. WHO. WHO policy recommendation on intermittent preventive treatment during infancy with sulphadoxine-pyrimethamine (SP-IPTi) for Plasmodium falciparum malaria control in Africa. 2010.

    Google Scholar 

  130. WHO. World Health Organization; WHO Evidence Review Group Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP). 2012.

    Google Scholar 

  131. Taylor SM, et al. Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study. Clin Infect Dis. 2012;55(1):42–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cravo P, et al. Antimalarial drugs clear resistant parasites from partially immune hosts. Antimicrob Agents Chemother. 2001;45(10):2897–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kinyanjui SM, et al. The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug. Am J Trop Med Hyg. 1999;60(6):943–7.

    Article  CAS  PubMed  Google Scholar 

  134. van Hensbroek MB, et al. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Trans R Soc Trop Med Hyg. 1995;89(6):672–6.

    Article  PubMed  Google Scholar 

  135. Wang P, Sims PF, Hyde JE. A modified in vitro sulfadoxine susceptibility assay for Plasmodium falciparum suitable for investigating Fansidar resistance. Parasitology. 1997;115(Pt 3):223–30.

    Article  CAS  PubMed  Google Scholar 

  136. Nzila A, et al. Chemosensitization of Plasmodium falciparum by probenecid in vitro. Antimicrob Agents Chemother. 2003;47(7):2108–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sowunmi A, et al. Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children. Trop Med Int Health. 2004;9(5):606–14.

    Article  CAS  PubMed  Google Scholar 

  138. Salcedo-Sora JE, et al. The molecular basis of folate salvage in Plasmodium falciparum: characterization of two folate transporters. J Biol Chem. 2011;286(52):44659–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nirmalan N, et al. Transcriptional analysis of genes encoding enzymes of the folate pathway in the human malaria parasite Plasmodium falciparum. Mol Microbiol. 2002;46(1):179–90.

    Article  CAS  PubMed  Google Scholar 

  140. Nirmalan N, Sims PF, Hyde JE. Translational up-regulation of antifolate drug targets in the human malaria parasite Plasmodium falciparum upon challenge with inhibitors. Mol Biochem Parasitol. 2004;136(1):63–70.

    Article  CAS  PubMed  Google Scholar 

  141. Nixon GL, et al. Antimalarial pharmacology and therapeutics of atovaquone. J Antimicrob Chemother. 2013;68(5):977–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4- (4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol. 1992;43(7):1545–53.

    Article  CAS  PubMed  Google Scholar 

  143. Syafruddin D, Siregar JE, Marzuki S. Mutations in the cytochrome b gene of Plasmodium berghei conferring resistance to atovaquone [In Process Citation]. Mol Biochem Parasitol. 1999;104(2):185–94.

    Article  CAS  PubMed  Google Scholar 

  144. Birth D, Kao WC, Hunte C. Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action. Nat Commun. 2014;5:4029.

    Article  CAS  PubMed  Google Scholar 

  145. Seymour KK, et al. dCTP levels are maintained in Plasmodium falciparum subjected to pyrimidine deficiency or excess. Ann Trop Med Parasitol. 1997;91(6):603–9.

    Article  CAS  PubMed  Google Scholar 

  146. Hammond DJ, Burchell JR, Pudney M. Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol Biochem Parasitol. 1985;14(1):97–109.

    Article  CAS  PubMed  Google Scholar 

  147. Painter HJ, et al. Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature. 2007;446(7131):88–91.

    Article  CAS  PubMed  Google Scholar 

  148. Bulusu V, Jayaraman V, Balaram H. Metabolic fate of fumarate, a side product of the purine salvage pathway in the intraerythrocytic stages of Plasmodium falciparum. J Biol Chem. 2011;286(11):9236–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Biagini GA, et al. Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proc Natl Acad Sci U S A. 2012;109(21):8298–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother. 1997;41(7):1413–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Sanz LM, et al. P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action. PLoS One. 2012;7(2):e30949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Lalloo DG, Hill DR. Preventing malaria in travellers. BMJ. 2008;336(7657):1362–6.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Dembele L, et al. Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery. PLoS One. 2011;6(3):e18162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Gassis S, Rathod PK. Frequency of drug resistance in Plasmodium falciparum: a nonsynergistic combination of 5-fluoroorotate and atovaquone suppresses in vitro resistance. Antimicrob Agents Chemother. 1996;40(4):914–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Rathod PK, McErlean T, Lee PC. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A. 1997;94(17):9389–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Srivastava IK, et al. Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Mol Microbiol. 1999;33(4):704–11.

    Article  CAS  PubMed  Google Scholar 

  157. Chiodini PL, et al. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother. 1995;36(6):1073–8.

    Article  CAS  PubMed  Google Scholar 

  158. Looareesuwan S, et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg. 1996;54(1):62–6.

    Article  CAS  PubMed  Google Scholar 

  159. Looareesuwan S, et al. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg. 1999;60(4):526–32.

    Article  CAS  PubMed  Google Scholar 

  160. Looareesuwan S, et al. Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med Hyg. 1999;60(4):533–41.

    Article  CAS  PubMed  Google Scholar 

  161. Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999;43(6):1334–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Korsinczky M, et al. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother. 2000;44(8):2100–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Fivelman QL, et al. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malar J. 2002;1(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Schwartz E, Bujanover S, Kain KC. Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin Infect Dis. 2003;37(3):450–1.

    Article  PubMed  Google Scholar 

  165. Fisher N, et al. Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc(1) catalytic turnover and protein expression. J Biol Chem. 2012;287(13):9731–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Schwobel B, et al. Different mutation patterns of atovaquone resistance to Plasmodium falciparum in vitro and in vivo: rapid detection of codon 268 polymorphisms in the cytochrome b as potential in vivo resistance marker. Malar J. 2003;2(1):5.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Gil JP, et al. Detection of atovaquone and Malarone resistance conferring mutations in Plasmodium falciparum cytochrome b gene (cytb). Mol Cell Probes. 2003;17(2–3):85–9.

    Article  CAS  PubMed  Google Scholar 

  168. Wichmann O, et al. Malarone treatment failure not associated with previously described mutations in the cytochrome b gene. Malar J. 2004;3(1):14.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Smilkstein MJ, et al. A drug-selected Plasmodium falciparum lacking the need for conventional electron transport. Mol Biochem Parasitol. 2008;159(1):64–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Pesole G, et al. Nucleotide substitution rate of mammalian mitochondrial genomes. J Mol Evol. 1999;48(4):427–34.

    Article  CAS  PubMed  Google Scholar 

  171. Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228(4703):1049–55.

    Article  CAS  PubMed  Google Scholar 

  172. O’Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin--the debate continues. Molecules. 2010;15(3):1705–21.

    Article  PubMed  CAS  Google Scholar 

  173. Meshnick SR, et al. Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu). Antimicrob Agents Chemother. 1993;37(5):1108–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Meshnick SR, et al. Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action. Mol Biochem Parasitol. 1991;49(2):181–9.

    Article  CAS  PubMed  Google Scholar 

  175. Posner GH, et al. Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin: the importance of a carbon-centered radical for antimalarial activity. J Med Chem. 1994;37(9):1256–8.

    Article  CAS  PubMed  Google Scholar 

  176. Posner GH, et al. Further evidence supporting the importance of and the restrictions on a carbon-centered radical for high antimalarial activity of 1,2,4-trioxanes like artemisinin. J Med Chem. 1995;38(13):2273–5.

    Article  CAS  PubMed  Google Scholar 

  177. Butler AR, et al. EPR evidence for the involvement of free radicals in the iron-catalysed decomposition of qinghaosu (artemisinin) and some derivatives; antimalarial action of some polycyclic endoperoxides. Free Radic Res. 1998;28(5):471–6.

    Article  CAS  PubMed  Google Scholar 

  178. O’Neill PM, et al. Biomimetic Fe(II)-mediated degradation of arteflene (Ro-42-1611). The first EPR spin-trapping evidence for the previously postulated secondary carbon-centered cyclohexyl radical. J Org Chem. 2000;65(5):1578–82.

    Article  PubMed  CAS  Google Scholar 

  179. Wu W-M, et al. Unified mechanistic framework for the Fe(II)-induced cleavage of Qinghaosu and derivatives/analogues. The first spin-trapping evidence for the previously postulated secondary C-4 radical. J Am Chem Soc. 1998;120(14):3316–25.

    Article  CAS  Google Scholar 

  180. Haynes RK, et al. The Fe2+-mediated decomposition, PfATP6 binding, and antimalarial activities of artemisone and other artemisinins: the unlikelihood of C-centered radicals as bioactive intermediates. ChemMedChem. 2007;2(10):1480–97.

    Article  CAS  PubMed  Google Scholar 

  181. Haynes RK, Pai HH-O, Voerste A. Ring opening of artemisinin (qinghaosu) and dihydroartemisinin and interception of the open hydroperoxides with Formation of N-oxides — a chemical model for antimalarial mode of action. Tetrahedron Lett. 1999;40(25):4715–8.

    Article  CAS  Google Scholar 

  182. Haynes RK, et al. Interactions between artemisinins and other antimalarial drugs in relation to the cofactor model--a unifying proposal for drug action. ChemMedChem. 2012;7(12):2204–26.

    Article  CAS  PubMed  Google Scholar 

  183. Li W, et al. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet. 2005;1(3):e36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Wang J, et al. Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS One. 2010;5(3):e9582.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Olliaro P. Mode of action and mechanisms of resistance for antimalarial drugs. Pharmacol Ther. 2001;89(2):207–19.

    Article  CAS  PubMed  Google Scholar 

  186. Golenser J, et al. Current perspectives on the mechanism of action of artemisinins. Int J Parasitol. 2006;36(14):1427–41.

    Article  CAS  PubMed  Google Scholar 

  187. Pandey AV, et al. Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite. J Biol Chem. 1999;274(27):19383–8.

    Article  CAS  PubMed  Google Scholar 

  188. Bhisutthibhan J, et al. The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J Biol Chem. 1998;273(26):16192–8.

    Article  CAS  PubMed  Google Scholar 

  189. Eckstein-Ludwig U, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424(6951):957–61.

    Article  CAS  PubMed  Google Scholar 

  190. Jiang JB, et al. Qinghaosu-induced changes in the morphology of Plasmodium inui. Am J Trop Med Hyg. 1985;34(3):424–8.

    Article  CAS  PubMed  Google Scholar 

  191. Kawai S, Kano S, Suzuki M. Morphologic effects of artemether on Plasmodium falciparum in Aotus trivirgatus. Am J Trop Med Hyg. 1993;49(6):812–8.

    Article  CAS  PubMed  Google Scholar 

  192. Maeno Y, et al. Morphologic effects of artemisinin in Plasmodium falciparum. Am J Trop Med Hyg. 1993;49(4):485–91.

    Article  CAS  PubMed  Google Scholar 

  193. Zhao Y, Hanton WK, Lee KH. Antimalarial agents, 2. Artesunate, an inhibitor of cytochrome oxidase activity in Plasmodium berghei. J Nat Prod. 1986;49(1):139–42.

    Article  CAS  PubMed  Google Scholar 

  194. Krungkrai J, et al. Mitochondrial oxygen consumption in asexual and sexual blood stages of the human malarial parasite, Plasmodium falciparum. Southeast Asian J Trop Med Public Health. 1999;30(4):636–42.

    CAS  PubMed  Google Scholar 

  195. del Pilar Crespo M, et al. Artemisinin and a series of novel endoperoxide antimalarials exert early effects on digestive vacuole morphology. Antimicrob Agents Chemother. 2008;52(1):98–109.

    Article  PubMed  CAS  Google Scholar 

  196. Antoine T, et al. Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential. J Antimicrob Chemother. 2014;69(4):1005–16.

    Article  CAS  PubMed  Google Scholar 

  197. Flegg JA, et al. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J. 2011;10:339.

    Article  PubMed  PubMed Central  Google Scholar 

  198. White NJ. The parasite clearance curve. Malar J. 2011;10:278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Mu J, et al. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nat Genet. 2010;42(3):268–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Witkowski B, et al. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis. 2013;13(12):1043–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Witkowski B, et al. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia. Antimicrob Agents Chemother. 2013;57(2):914–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Ariey F, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505(7481):50–5.

    Article  PubMed  CAS  Google Scholar 

  203. Cheeseman IH, et al. A major genome region underlying artemisinin resistance in malaria. Science. 2012;336(6077):79–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Takala-Harrison S, et al. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci U S A. 2013;110(1):240–5.

    Article  CAS  PubMed  Google Scholar 

  205. Miotto O, et al. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet. 2013;45(6):648–55.

    Article  CAS  PubMed  Google Scholar 

  206. Amaratunga C, et al. Artemisinin resistance in Plasmodium falciparum. Lancet Infect Dis. 2014;14(6):449–50.

    Article  PubMed  PubMed Central  Google Scholar 

  207. Straimer J, et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347(6220):428–31.

    Article  CAS  PubMed  Google Scholar 

  208. Mbengue A, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature. 2015;520:683–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Tucker MS, et al. Phenotypic and genotypic analysis of in vitro-selected artemisinin-resistant progeny of Plasmodium falciparum. Antimicrob Agents Chemother. 2012;56(1):302–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Teuscher F, et al. Phenotypic changes in artemisinin-resistant Plasmodium falciparum lines in vitro: evidence for decreased sensitivity to dormancy and growth inhibition. Antimicrob Agents Chemother. 2012;56(1):428–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Klonis N, et al. Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci U S A. 2011;108(28):11405–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Mok S, et al. Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science. 2015;347(6220):431–5.

    Article  CAS  PubMed  Google Scholar 

  213. WHO. Chemotherapy of malaria. Report of a WHO scientific group. Geneva, World Health Organization (WHO Technical Report Series, No. 375); 1967.

    Google Scholar 

  214. Bruce-Chwatt LJ, et al. Chemotherapy of malaria. Rev. 2nd ed. Geneva: World Health Organization; 1986.

    Google Scholar 

  215. Solmaz SR, Hunte C. Structure of complex III with bound cytochrome c in reduced state and definition of a minimal core interface for electron transfer. J Biol Chem. 2008;283(25):17542–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

GAB and SAW acknowledge the support of the Wellcome Trust and the MRC.

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Authors and Affiliations

  1. Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK

    Giancarlo A. Biagini Ph.D. & Stephen A. Ward Ph.D.

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  1. Giancarlo A. Biagini Ph.D.
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  2. Stephen A. Ward Ph.D.
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Correspondence to Giancarlo A. Biagini Ph.D. .

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Editors and Affiliations

  1. Treiber Therapeutics, Cambridge, Massachusetts, USA

    Douglas L. Mayers

  2. Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA

    Jack D. Sobel

  3. Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada

    Marc Ouellette

  4. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Keith S. Kaye

  5. Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Dror Marchaim

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Biagini, G.A., Ward, S.A. (2017). Mechanisms of Antimalarial Drug Resistance. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_41

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