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Tackling the Problem of Antimalarial Resistance

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Drug Discovery in Africa

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Abstract

The emergence and spread of resistance remain a burgeoning problem in the control and the management of malaria. Effort has been dedicated in discovering and developing new drugs; however, these efforts are hampered by the rapid selection of resistance. For instance, there is no single antimalarial in clinical use against which the parasite has not yet developed resistance. To counterbalance this rapid development of resistance, not only should new drugs be developed, but the mechanisms of resistance to existing drugs need to be fully understood. Indeed, understanding these mechanisms could lead to identifying simple ways, by the use of single markers, to map and monitor the emergence and spread of drug resistance. In addition, such studies could also contribute to clarifying the mode of action drug, which eventually could lead to the discovery of new targets and thus new drugs. In this chapter, we have reviewed our current knowledge and presented existing challenges and gaps, on the mechanisms of resistance to most clinically important antimalarials.

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Abbreviations

ACT:

Artemisinin Combination Therapy

ATM:

Artemether

AQ:

Amodiaquine

Art-D:

Artemisinin derivatives

ART:

Artesunate

CQ:

Chloroquine

CVIET:

Cysteine at position 72, valine at position 73, isoleucine at 74, glutamic acid at 75 and threonine at 76

CVIDT:

Cysteine at position 72, valine at position 73, isoleucine at 74, aspartic acid at 75 and threonine at 76

CVIKT:

Cysteine at position 72, valine at position 73, isoleucine at 74, lysine at 75 and threonine at 76

DEAQ:

Desethyl-amodiaquine

DHA:

Dihydroartemisinin

DHPS:

Dihydropteroate synthase

DHFR:

Dihydrofolate reductase

DV:

Digestive vacuole

dUMP:

Deoxyuridine monophosphate

DDS:

Dapsone

GTP-CH:

Guanosine triphosphate cyclohydrolase

HFT:

Halofantrine

ITP:

Preventive treatment in pregnancy

PM/SD:

Pyrimethamine/sulfadoxine

LM:

Lumefantrine

MFQ:

Mefloquine

QN:

Quinine

PQ:

Piperaquine

pABA:

Paraminobenzoic acid

Pfcrt:

Plasmodium falciparum chloroquine resistance transporter

Pfmdr1:

Plasmodium falciparum multidrug resistance gene 1

QTL:

Quantitative trait loci

SD:

Sulphadoxine

SNP:

Single nucleotide polymorphism

SERCA:

Sarco/endoplasmic reticulum Ca2+ ATPases (SERCAs)

SVMNT:

Serine at position 72, valine at position 73, methionine at 74, asparagine at 75 and threonine at 76

VPM:

Verapamil

References

  1. Nzila A (2006) Inhibitors of de novo folate enzymes in Plasmodium falciparum. Drug Discov Today 11:939–944

    Article  CAS  Google Scholar 

  2. Makanga M, Krudsood S (2009) The clinical efficacy of artemether/lumefantrine (Coartemâ„¢). Malar J 8(Suppl 1):S5

    Article  CAS  Google Scholar 

  3. Adjei GO, Goka BQ, Binka F et al (2009) Artemether-lumefantrine: an oral antimalarial for uncomplicated malaria in children. Expert Rev Anti Infect Ther 7:669–681

    Article  CAS  Google Scholar 

  4. Kokwaro G, Mwai L, Nzila A (2007) Artemether/lumefantrine in the treatment of uncomplicated falciparum malaria. Expert Opin Pharmacother 8:75–94

    Article  CAS  Google Scholar 

  5. Sisowath C, Petersen I, Veiga MI et al (2009) In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa. J Infect Dis 199:750–757

    Article  CAS  Google Scholar 

  6. Dokomajilar C, Nsobya SL, Greenhouse B et al (2006) Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrob Agents Chemother 50:1893–1895

    Article  CAS  Google Scholar 

  7. Some AF, Sere YY, Dokomajilar C et al (2010) Selection of known Plasmodium falciparum resistance-mediating polymorphisms by artemether-lumefantrine and amodiaquine-sulfadoxine-pyrimethamine but not dihydroartemisinin-piperaquine in Burkina Faso. Antimicrob Agents Chemother 54:1949–1954

    Article  CAS  Google Scholar 

  8. Mwai L, Kiara SM, Abdirahman A et al (2009) In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrob Agents Chemother 53:5069–5073

    Article  CAS  Google Scholar 

  9. Sirima SB, Gansane A (2007) Artesunate-amodiaquine for the treatment of uncomplicated malaria. Expert Opin Investig Drugs 16:1079–1085

    Article  CAS  Google Scholar 

  10. Zwang J, Olliaro P, Barennes H et al (2009) Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis. Malar J 8:203

    Article  CAS  Google Scholar 

  11. Mutabingwa TK, Anthony D, Heller A et al (2005) Amodiaquine alone, amodiaquine+ sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet 365:1474–1480

    Article  CAS  Google Scholar 

  12. Sasi P, Abdulrahaman A, Mwai L et al (2009) In vivo and in vitro efficacy of amodiaquine against Plasmodium falciparum in an area of continued use of 4-aminoquinolines in East Africa. J Infect Dis 199:1575–1582

    Article  CAS  Google Scholar 

  13. Dondorp AM, Fanello CI, Hendriksen IC et al (2010) Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 376:1647–1657

    Article  CAS  Google Scholar 

  14. Anonymous (2010) WHO. Guidelines for the treatment of malaria, second edition. http://www.who.int/malaria/publications/atoz/9789241547925/en/index. WHO, Accessed 12 Jan 2011, p 18

  15. Okombo J, Kiara SM, Rono J et al (2010) In vitro activities of quinine and other antimalarials and pfnhe polymorphisms in Plasmodium isolates from Kenya. Antimicrob Agents Chemother 54:3302–3307

    Article  CAS  Google Scholar 

  16. Anonymous. http://www.mmv.org/sites/default/files/uploads/docs/essential_info_for_-scientists/3Q_Global_Malaria_Portfolio_Slide_by_therapeutic_type.ppt. Accessed 15 Oct 2010

  17. Dondorp AM, Nosten F, Yi P et al (2009) Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361:455–467

    Article  CAS  Google Scholar 

  18. Nuwaha F (2001) The challenge of chloroquine-resistant malaria in sub-Saharan Africa. Health Policy Plan 16:1–12

    Article  CAS  Google Scholar 

  19. Su X, Kirkman LA, Fujioka H et al (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

    Article  CAS  Google Scholar 

  20. Djimde A, Doumbo OK, Cortese JF et al (2001) A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344:257–263

    Article  CAS  Google Scholar 

  21. Sanchez CP, Dave A, Stein WD et al (2010) Transporters as mediators of drug resistance in Plasmodium falciparum. Int J Parasitol 40:1109–1118

    Article  CAS  Google Scholar 

  22. Sanchez CP, Stein WD, Lanzer M (2007) Is PfCRT a channel or a carrier? Two competing models explaining chloroquine resistance in Plasmodium falciparum. Trends Parasitol 23:332–339

    Article  CAS  Google Scholar 

  23. Valderramos SG, Fidock DA (2006) Transporters involved in resistance to antimalarial drugs. Trends Pharmacol Sci 27:594–601

    Article  CAS  Google Scholar 

  24. Cooper RA, Hartwig CL, Ferdig MT (2005) pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective. Acta Trop 94:170–180

    Article  CAS  Google Scholar 

  25. Picot S, Olliaro P, de Monbrison F et al (2009) A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malar J 8:89

    Article  CAS  Google Scholar 

  26. Duraisingh MT, Cowman AF (2005) Contribution of the pfmdr1 gene to antimalarial drug-resistance. Acta Trop 94:181–190

    Article  CAS  Google Scholar 

  27. Egan TJ, Kaschula CH (2007) Strategies to reverse drug resistance in malaria. Curr Opin Infect Dis 20:598–604

    Article  CAS  Google Scholar 

  28. Henry M, Alibert S, Orlandi-Pradines E et al (2006) Chloroquine resistance reversal agents as promising antimalarial drugs. Curr Drug Targets 7:935–948

    Article  CAS  Google Scholar 

  29. van Schalkwyk DA, Walden JC, Smith PJ (2001) Reversal of chloroquine resistance in Plasmodium falciparum using combinations of chemosensitizers. Antimicrob Agents Chemother 45:3171–3174

    Article  Google Scholar 

  30. Gbotosho GO, Happi CT, Sijuade A et al (2008) Comparative study of interactions between chloroquine and chlorpheniramine or promethazine in healthy volunteers: a potential combination-therapy phenomenon for resuscitating chloroquine for malaria treatment in Africa. Ann Trop Med Parasitol 102:3–9

    Article  CAS  Google Scholar 

  31. Sowunmi A, Adedeji AA, Gbotosho GO et al (2006) Effects of pyrimethamine-sulphadoxine, chloroquine plus chlorpheniramine, and amodiaquine plus pyrimethamine-sulphadoxine on gametocytes during and after treatment of acute, uncomplicated malaria in children. Mem Inst Oswaldo Cruz 101:887–893

    Article  CAS  Google Scholar 

  32. Sowunmi A, Fateye BA, Adedeji AA et al (2005) Predictors of the failure of treatment with chloroquine in children with acute, uncomplicated, Plasmodium falciparum malaria, in an area with high and increasing incidences of chloroquine resistance. Ann Trop Med Parasitol 99:535–544

    Article  CAS  Google Scholar 

  33. Ciach M, Zong K, Kain KC et al (2003) Reversal of mefloquine and quinine resistance in Plasmodium falciparum with NP30. Antimicrob Agents Chemother 47:2393–2396

    Article  CAS  Google Scholar 

  34. Lehane AM, Hayward R, Saliba KJ et al (2008) A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites. J Cell Sci 121:1624–1632

    Article  CAS  Google Scholar 

  35. Martin SK, Oduola AM, Milhous WK (1987) Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235:899–901

    Article  CAS  Google Scholar 

  36. Martiney JA, Cerami A, Slater AF (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

    Article  CAS  Google Scholar 

  37. Austin DJ, Anderson RM (1999) Studies of antibiotic resistance within the patient, hospitals and the community using simple mathematical models. Philos Trans R Soc Lond B Biol Sci 354:721–738

    Article  CAS  Google Scholar 

  38. Lenski RE (1998) Bacterial evolution and the cost of antibiotic resistance. Int Microbiol 1:265–270

    CAS  Google Scholar 

  39. Legrand E, Volney B, Meynard JB et al (2008) In vitro monitoring of Plasmodium falciparum drug resistance in French Guiana: a synopsis of continuous assessment from 1994 to 2005. Antimicrob Agents Chemother 52:288–298

    Article  CAS  Google Scholar 

  40. Schwenke A, Brandts C, Philipps J et al (2001) Declining chloroquine resistance of Plasmodium falciparum in Lambarene, Gabon from 1992 to 1998. Wien Klin Wochenschr 113:63–64

    CAS  Google Scholar 

  41. Liu DQ, Liu RJ, Ren DX et al (1995) Changes in the resistance of Plasmodium falciparum to chloroquine in Hainan, China. Bull World Health Organ 73:483–486

    CAS  Google Scholar 

  42. Laufer MK, Takala-Harrison S, Dzinjalamala FK et al (2010) Return of chloroquine-susceptible falciparum malaria in Malawi was a reexpansion of diverse susceptible parasites. J Infect Dis 202:801–808

    Article  Google Scholar 

  43. Laufer MK, Thesing PC, Eddington ND et al (2006) Return of chloroquine antimalarial efficacy in Malawi. N Engl J Med 355:1959–1966

    Article  CAS  Google Scholar 

  44. Kublin JG, Cortese JF, Njunju EM et al (2003) Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 187:1870–1875

    Article  Google Scholar 

  45. Mita T, Kaneko A, Lum JK 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

    CAS  Google Scholar 

  46. Mwai L, Ochong E, Abdirahman A et al (2009) Chloroquine resistance before and after its withdrawal in Kenya. Malar J 8:106

    Article  CAS  Google Scholar 

  47. Jullien V, Ogutu B, Juma E et al (2010) Population pharmacokinetics and pharmacodynamic considerations of amodiaquine and desethylamodiaquine in Kenyan adults with uncomplicated malaria receiving artesunate-amodiaquine combination therapy. Antimicrob Agents Chemother 54:2611–2617

    Article  CAS  Google Scholar 

  48. Stepniewska K, Taylor W, Sirima SB et al (2009) Population pharmacokinetics of artesunate and amodiaquine in African children. Malar J 8:200

    Article  CAS  Google Scholar 

  49. Basco LK, Ringwald P (2007) Molecular epidemiology of malaria in Cameroon. XXIV. Trends of in vitro antimalarial drug responses in Yaounde, Cameroon. Am J Trop Med Hyg 76:20–26

    CAS  Google Scholar 

  50. Tinto H, Rwagacondo C, Karema C et al (2006) In vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, dihydroartemisinin and quinine in an area of high chloroquine resistance in Rwanda. Trans R Soc Trop Med Hyg 100:509–514

    Article  CAS  Google Scholar 

  51. Mbacham WF, Evehe MS, Netongo PM et al (2010) Efficacy of amodiaquine, sulphadoxine-pyrimethamine and their combination for the treatment of uncomplicated Plasmodium falciparum malaria in children in Cameroon at the time of policy change to artemisinin-based combination therapy. Malar J 9:34

    Article  CAS  Google Scholar 

  52. Echeverry DF, Holmgren G, Murillo C et al (2007) Short report: polymorphisms in the pfcrt and pfmdr1 genes of Plasmodium falciparum and in vitro susceptibility to amodiaquine and desethylamodiaquine. Am J Trop Med Hyg 77:1034–1038

    CAS  Google Scholar 

  53. Nsobya SL, Dokomajilar C, Joloba M et al (2007) Resistance-mediating Plasmodium falciparum pfcrt and pfmdr1 alleles after treatment with artesunate-amodiaquine in Uganda. Antimicrob Agents Chemother 51:3023–3025

    Article  CAS  Google Scholar 

  54. Happi CT, Gbotosho GO, Folarin OA et al (2006) Association between mutations in Plasmodium falciparum chloroquine resistance transporter and P. falciparum multidrug resistance 1 genes and in vivo amodiaquine resistance in P. falciparum malaria-infected children in Nigeria. Am J Trop Med Hyg 75:155–161

    CAS  Google Scholar 

  55. Holmgren G, Gil JP, Ferreira PM et al (2006) Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infect Genet Evol 6:309–314

    Article  CAS  Google Scholar 

  56. Ochong EO, van den Broek IV, Keus K et al (2003) Short report: association between chloroquine and amodiaquine resistance and allelic variation in the Plasmodium falciparum multiple drug resistance 1 gene and the chloroquine resistance transporter gene in isolates from the upper Nile in southern Sudan. Am J Trop Med Hyg 69:184–187

    CAS  Google Scholar 

  57. Sa JM, Twu O, Hayton K et al (2009) Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proc Natl Acad Sci USA 106:18883–18889

    Article  CAS  Google Scholar 

  58. Alifrangis M, Dalgaard MB, Lusingu JP et al (2006) Occurrence of the Southeast Asian/South American SVMNT haplotype of the chloroquine-resistance transporter gene in Plasmodium falciparum in Tanzania. J Infect Dis 193:1738–1741

    Article  CAS  Google Scholar 

  59. Sa JM, Twu O (2010) Protecting the malaria drug arsenal: halting the rise and spread of amodiaquine resistance by monitoring the PfCRT SVMNT type. Malar J 9:374

    Article  Google Scholar 

  60. Sisowath C, Ferreira PE, Bustamante LY et al (2007) The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Trop Med Int Health 12:736–742

    Article  CAS  Google Scholar 

  61. Humphreys GS, Merinopoulos I, Ahmed J et al (2007) Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrob Agents Chemother 51:991–997

    Article  CAS  Google Scholar 

  62. Sisowath C, Stromberg J, Martensson A et al (2005) In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem™). J Infect Dis 191:1014–1017

    Article  CAS  Google Scholar 

  63. Nsobya SL, Kiggundu M, Nanyunja S et al (2010) In vitro sensitivities of Plasmodium falciparum to different antimalarial drugs in Uganda. Antimicrob Agents Chemother 54:1200–1206

    Article  CAS  Google Scholar 

  64. Price RN, Uhlemann AC, van Vugt M et al (2006) Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis 42:1570–1577

    Article  CAS  Google Scholar 

  65. Price RN, Uhlemann AC, Brockman A et al (2004) Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364:438–447

    Article  CAS  Google Scholar 

  66. Okombo J, Ohuma E, Picot S et al (2011) Update on genetic markers of quinine resistance in Plasmodium falciparum. Mol Biochem Parasitol 177:77–82

    Article  CAS  Google Scholar 

  67. Praygod G, de Frey A, Eisenhut M (2008) Artemisinin derivatives versus quinine in treating severe malaria in children: a systematic review. Malar J 7:210

    Article  CAS  Google Scholar 

  68. Jones KL, Donegan S, Lalloo DG (2007) Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev CD005967

    Google Scholar 

  69. Myint HY, Tipmanee P, Nosten F et al (2004) A systematic overview of published antimalarial drug trials. Trans R Soc Trop Med Hyg 98:73–81

    Article  Google Scholar 

  70. Achan J, Tibenderana JK, Kyabayinze D et al (2009) Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial. BMJ 339:b2763

    Article  Google Scholar 

  71. Adam I, Salih I, Elbashir MI (2005) Quinine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. Trans R Soc Trop Med Hyg 99:736–738

    Article  CAS  Google Scholar 

  72. Adegnika AA, Breitling LP, Agnandji ST et al (2005) Effectiveness of quinine monotherapy for the treatment of Plasmodium falciparum infection in pregnant women in Lambarene, Gabon. Am J Trop Med Hyg 73:263–266

    CAS  Google Scholar 

  73. de Vries PJ, Bich NN, Van Thien H et al (2000) Combinations of artemisinin and quinine for uncomplicated falciparum malaria: efficacy and pharmacodynamics. Antimicrob Agents Chemother 44:1302–1308

    Article  Google Scholar 

  74. McGready R, Ashley EA, Moo E et al (2005) A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J Infect Dis 192:846–853

    Article  CAS  Google Scholar 

  75. Basco LK, Le Bras J (1993) In vitro activity of chloroquine and quinine in combination with desferrioxamine against Plasmodium falciparum. Am J Hematol 42:389–391

    Article  CAS  Google Scholar 

  76. Brasseur P, Kouamouo J, Moyou RS et al (1992) Mefloquine resistant malaria in Cameroon and correlation with resistance to quinine. Mem Inst Oswaldo Cruz 87(Suppl 3):271–273

    Article  Google Scholar 

  77. Brasseur P, Kouamouo J, Moyou-Somo R et al (1992) Multi-drug resistant falciparum malaria in Cameroon in 1987–1988. II. Mefloquine resistance confirmed in vivo and in vitro and its correlation with quinine resistance. Am J Trop Med Hyg 46:8–14

    CAS  Google Scholar 

  78. Simon F, Le Bras J, Charmot G et al (1986) Severe chloroquine-resistant falciparum malaria in Gabon with decreased sensitivity to quinine. Trans R Soc Trop Med Hyg 80:996–997

    Article  CAS  Google Scholar 

  79. Warsame M, Wernsdorfer WH, Payne D et al (1991) Susceptibility of Plasmodium falciparum in vitro to chloroquine, mefloquine, quinine and sulfadoxine/pyrimethamine in Somalia: relationships between the responses to the different drugs. Trans R Soc Trop Med Hyg 85:565–569

    Article  CAS  Google Scholar 

  80. Uhlemann AC, Krishna S (2005) Antimalarial multi-drug resistance in Asia: mechanisms and assessment. Curr Top Microbiol Immunol 295:39–53

    Article  CAS  Google Scholar 

  81. Andriantsoanirina V, Menard D, Rabearimanana S et al (2010) Association of microsatellite variations of Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene with reduced in vitro susceptibility to quinine: lack of confirmation in clinical isolates from Africa. Am J Trop Med Hyg 82:782–787

    Article  CAS  Google Scholar 

  82. Chaijaroenkul W, Wisedpanichkij R, Na-Bangchang K (2010) Monitoring of in vitro susceptibilities and molecular markers of resistance of Plasmodium falciparum isolates from Thai-Myanmar border to chloroquine, quinine, mefloquine and artesunate. Acta Trop 113:190–194

    Article  CAS  Google Scholar 

  83. Lakshmanan V, Bray PG, Verdier-Pinard D et al (2005) A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J 24:2294–2305

    Article  CAS  Google Scholar 

  84. Sidhu AB, Verdier-Pinard D, Fidock DA (2002) Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298:210–213

    Article  CAS  Google Scholar 

  85. Woodrow CJ, Krishna S (2006) Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance. Cell Mol Life Sci 63:1586–1596

    Article  CAS  Google Scholar 

  86. Ferdig MT, Cooper RA, Mu J et al (2004) Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol 52:985–997

    Article  CAS  Google Scholar 

  87. Reed MB, Saliba KJ, Caruana SR et al (2000) Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403:906–909

    Article  CAS  Google Scholar 

  88. Sidhu AB, Valderramos SG, Fidock DA (2005) Pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Mol Microbiol 57:913–926

    Article  CAS  Google Scholar 

  89. Pickard AL, Wongsrichanalai C, Purfield A et al (2003) Resistance to antimalarials in Southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob Agents Chemother 47:2418–2423

    Article  CAS  Google Scholar 

  90. Anderson TJ, Nair S, Qin H et al (2005) Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance? Antimicrob Agents Chemother 49:2180–2188

    Article  CAS  Google Scholar 

  91. Sidhu AB, Uhlemann AC, Valderramos SG et al (2006) Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis 194:528–535

    Article  Google Scholar 

  92. Mu J, Ferdig MT, Feng X et al (2003) Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol Microbiol 49:977–989

    Article  CAS  Google Scholar 

  93. Yang Z, Li C, Miao M et al (2011) Multidrug-resistant genotypes of Plasmodium falciparum, Myanmar. Emerg Infect Dis 17:498–501

    Article  Google Scholar 

  94. Baliraine FN, Nsobya SL, Achan J et al (2011) Limited ability of Plasmodium falciparum pfcrt, pfmdr1, and pfnhe1 polymorphisms to predict quinine in vitro sensitivity or clinical effectiveness in Uganda. Antimicrob Agents Chemother 55:615–622

    Article  CAS  Google Scholar 

  95. Briolant S, Pelleau S, Bogreau H et al (2011) In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo. Malar J 10:37

    Article  CAS  Google Scholar 

  96. Henry M, Briolant S, Zettor A et al (2009) Plasmodium falciparum Na+/H+ exchanger 1 transporter is involved in reduced susceptibility to quinine. Antimicrob Agents Chemother 53:1926–1930

    Article  CAS  Google Scholar 

  97. Meng H, Zhang R, Yang H et al (2010) In vitro sensitivity of Plasmodium falciparum clinical isolates from the China-Myanmar border area to quinine and association with polymorphism in the Na+/H+ exchanger. Antimicrob Agents Chemother 54:4306–4313

    Article  CAS  Google Scholar 

  98. Nkrumah LJ, Riegelhaupt PM, Moura P et al (2009) Probing the multifactorial basis of Plasmodium falciparum quinine resistance: evidence for a strain-specific contribution of the sodium-proton exchanger PfNHE. Mol Biochem Parasitol 165:122–131

    Article  CAS  Google Scholar 

  99. Bukirwa H, Orton L (2005) Artesunate plus mefloquine versus mefloquine for treating uncomplicated malaria. Cochrane Database Syst Rev CD004531

    Google Scholar 

  100. Croft AM, Garner P (2008) WITHDRAWN: mefloquine for preventing malaria in non-immune adult travellers. Cochrane Database Syst Rev CD000138

    Google Scholar 

  101. Schlagenhauf P, Adamcova M, Regep L et al (2010) The position of mefloquine as a 21st century malaria chemoprophylaxis. Malar J 9:357

    Article  Google Scholar 

  102. Toovey S, Bustamante LY, Uhlemann AC et al (2008) Effect of artemisinins and amino alcohol partner antimalarials on mammalian sarcoendoplasmic reticulum calcium adenosine triphosphatase activity. Basic Clin Pharmacol Toxicol 103:209–213

    Article  CAS  Google Scholar 

  103. Henry M, Diallo I, Bordes J et al (2006) Urban malaria in Dakar, Senegal: chemosusceptibility and genetic diversity of Plasmodium falciparum isolates. Am J Trop Med Hyg 75:146–151

    CAS  Google Scholar 

  104. Pradines B, Hovette P, Fusai T et al (2006) Prevalence of in vitro resistance to eleven standard or new antimalarial drugs among Plasmodium falciparum isolates from Pointe-Noire, Republic of the Congo. J Clin Microbiol 44:2404–2408

    Article  CAS  Google Scholar 

  105. Ramharter M, Wernsdorfer WH, Kremsner PG (2004) In vitro activity of quinolines against Plasmodium falciparum in Gabon. Acta Trop 90:55–60

    Article  CAS  Google Scholar 

  106. Randrianarivelojosia M, Randrianasolo L, Randremanana RV et al (2004) Susceptibility of Plasmodium falciparum to the drugs used to treat severe malaria (quinine) and to prevent malaria (mefloquine, cycloguanil) in Comoros Union and Madagascar. S Afr Med J 94:47–51

    CAS  Google Scholar 

  107. Ndong JM, Atteke C, Aubouy A et al (2003) In vitro activity of chloroquine, quinine, mefloquine and halofantrine against Gabonese isolates of Plasmodium falciparum. Trop Med Int Health 8:25–29

    Article  CAS  Google Scholar 

  108. Yavo W, Bla KB, Djaman AJ et al (2010) In vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, quinine, mefloquine and halofantrine in Abidjan (Cote d'Ivoire). Afr Health Sci 10:111–116

    CAS  Google Scholar 

  109. Adam I, Ali DA, Alwaseila A et al (2004) Mefloquine in the treatment of falciparum malaria during pregnancy in Eastern Sudan. Saudi Med J 25:1400–1402

    Google Scholar 

  110. Aubouy A, Fievet N, Bertin G et al (2007) Dramatically decreased therapeutic efficacy of chloroquine and sulfadoxine-pyrimethamine, but not mefloquine, in southern Benin. Trop Med Int Health 12:886–894

    Article  CAS  Google Scholar 

  111. Bouyou-Akotet MK, Ramharter M, Ngoungou EB et al (2010) Efficacy and safety of a new pediatric artesunate-mefloquine drug formulation for the treatment of uncomplicated falciparum malaria in Gabon. Wien Klin Wochenschr 122:173–178

    Article  CAS  Google Scholar 

  112. Faye B, Ndiaye JL, Tine R et al (2010) A randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children. Am J Trop Med Hyg 82:140–144

    Article  CAS  Google Scholar 

  113. Sowunmi A, Gbotosho GO, Happi C et al (2009) Therapeutic efficacy and effects of artesunate-mefloquine and mefloquine alone on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria. Am J Trop Med Hyg 81:979–986

    Article  CAS  Google Scholar 

  114. Tietche F, Chelo D, Mina Ntoto NK et al (2010) Tolerability and efficacy of a pediatric granule formulation of artesunate-mefloquine in young children from Cameroon with uncomplicated falciparum malaria. Am J Trop Med Hyg 82:1034–1040

    Article  CAS  Google Scholar 

  115. Fryauff DJ, Owusu-Agyei S, Utz G et al (2007) Mefloquine treatment for uncomplicated falciparum malaria in young children 6-24 months of age in northern Ghana. Am J Trop Med Hyg 76:224–231

    CAS  Google Scholar 

  116. Barends M, Jaidee A, Khaohirun N et al (2007) In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border. Malar J 6:81

    Article  CAS  Google Scholar 

  117. Huttinger F, Satimai W, Wernsdorfer G et al (2010) Sensitivity to artemisinin, mefloquine and quinine of Plasmodium falciparum in northwestern Thailand. Wien Klin Wochenschr 122(Suppl 3):52–56

    Article  CAS  Google Scholar 

  118. Noedl H, Krudsood S, Leowattana W et al (2007) In vitro antimalarial activity of azithromycin, artesunate, and quinine in combination and correlation with clinical outcome. Antimicrob Agents Chemother 51:651–656

    Article  CAS  Google Scholar 

  119. Oduola AM, Milhous WK, Weatherly NF et al (1988) Plasmodium falciparum: induction of resistance to mefloquine in cloned strains by continuous drug exposure in vitro. Exp Parasitol 67:354–360

    Article  CAS  Google Scholar 

  120. Wilson CM, Volkman SK, Thaithong S et al (1993) Amplification of pfmdr 1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand. Mol Biochem Parasitol 57:151–160

    Article  CAS  Google Scholar 

  121. Cowman AF, Galatis D, Thompson JK (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

    Article  CAS  Google Scholar 

  122. Price RN, Cassar C, Brockman A et al (1999) The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob Agents Chemother 43:2943–2949

    CAS  Google Scholar 

  123. Nothdurft HD, Clemens R, Bock HL et al (1993) Halofantrine: a new substance for treatment of multidrug-resistant malaria. Clin Investig 71:69–73

    Article  CAS  Google Scholar 

  124. Bryson HM, Goa KL (1992) Halofantrine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic potential. Drugs 43:236–258

    Article  CAS  Google Scholar 

  125. Brasseur P, Bitsindou P, Moyou RS et al (1993) Fast emergence of Plasmodium falciparum resistance to halofantrine. Lancet 341:901–902

    Article  CAS  Google Scholar 

  126. Basco LK (1993) Halofantrine resistance in African countries. Lancet 341:1283

    Article  CAS  Google Scholar 

  127. Carme B, Gay F, Hayette MP et al (1993) Halofantrine resistance in African countries. Lancet 341:1282–1283

    Article  CAS  Google Scholar 

  128. Chavchich M, Gerena L, Peters J et al (2010) Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum. Antimicrob Agents Chemother 54:2455–2464

    Article  CAS  Google Scholar 

  129. Kim HS, Okuda Y, Begum K et al (2001) Analysis of Pfmdr 1 gene in mefloquine-resistant Plasmodium falciparum. Nucleic Acids Res Suppl (1):231–232

    Google Scholar 

  130. Van Tyne D, Park DJ, Schaffner SF et al (2011) Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum. PLoS Genet 7:e1001383

    Article  CAS  Google Scholar 

  131. Beese SE, Negishi T, Levin DE (2009) Identification of positive regulators of the yeast fps1 glycerol channel. PLoS Genet 5:e1000738

    Article  CAS  Google Scholar 

  132. Geisler M, Girin M, Brandt S et al (2004) Arabidopsis immunophilin-like TWD1 functionally interacts with vacuolar ABC transporters. Mol Biol Cell 15:3393–3405

    Article  CAS  Google Scholar 

  133. Miletti-Gonzalez KE, Chen S, Muthukumaran N et al (2005) The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res 65:6660–6667

    Article  CAS  Google Scholar 

  134. Maude RJ, Pontavornpinyo W, Saralamba S et al (2009) The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J 8:31

    Article  CAS  Google Scholar 

  135. Li J, Zhou B (2010) Biological actions of artemisinin: insights from medicinal chemistry studies. Molecules 15:1378–1397

    Article  CAS  Google Scholar 

  136. Eastman RT, Fidock DA (2009) Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol 7:864–874

    CAS  Google Scholar 

  137. White NJ (2004) Antimalarial drug resistance. J Clin Investig 113:1084–1092

    CAS  Google Scholar 

  138. Anonymous (2011) WHO GPARC. http://www.who.int/malaria/publications/atoz/9789241500838/en/index.html

  139. Dondorp AM, Yeung S, White L et al (2010) Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol 8:272–280

    Article  CAS  Google Scholar 

  140. Ding XC, Beck HP, Raso G (2011) Plasmodium sensitivity to artemisinins: magic bullets hit elusive targets. Trends Parasitol 27:73–81

    Article  CAS  Google Scholar 

  141. Eckstein-Ludwig U, Webb RJ, Van Goethem ID et al (2003) Artemisinins target the SERCA of Plasmodium falciparum. Nature 424:957–961

    Article  CAS  Google Scholar 

  142. Uhlemann AC, Cameron A, Eckstein-Ludwig U et al (2005) A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat Struct Mol Biol 12:628–629

    Article  CAS  Google Scholar 

  143. Valderramos SG, Scanfeld D, Uhlemann AC et al (2010) Investigations into the role of the Plasmodium falciparum SERCA (PfATP6) L263E mutation in artemisinin action and resistance. Antimicrob Agents Chemother 54:3842–3852

    Article  CAS  Google Scholar 

  144. Jambou R, Legrand E, Niang M et al (2005) Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 366:1960–1963

    Article  CAS  Google Scholar 

  145. Ibrahim ML, Khim N, Adam HH et al (2009) Polymorphism of PfATPase in Niger: detection of three new point mutations. Malar J 8:28

    Article  CAS  Google Scholar 

  146. Codd A, Teuscher F, Kyle DE et al (2011) Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure. Malar J 10:56

    Article  Google Scholar 

  147. Teuscher F, Gatton ML, Chen N et al (2010) Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J Infect Dis 202:1362–1368

    Article  Google Scholar 

  148. Witkowski B, Lelievre J, Barragan MJ et al (2010) Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob Agents Chemother 54:1872–1877

    Article  CAS  Google Scholar 

  149. Nzila A (2006) The past, present and future of antifolates in the treatment of Plasmodium falciparum infection. J Antimicrob Chemother 57:1043–1054

    Article  CAS  Google Scholar 

  150. Premji Z, Umeh RE, Owusu-Agyei S et al (2009) Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind Phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria. PLoS One 4:e6682

    Article  CAS  Google Scholar 

  151. Tiono AB, Dicko A, Ndububa DA et al (2009) Chlorproguanil-dapsone-artesunate versus chlorproguanil-dapsone: a randomized, double-blind, Phase III trial in African children, adolescents, and adults with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 81:969–978

    Article  CAS  Google Scholar 

  152. Nakato H, Vivancos R, Hunter PR (2007) A systematic review and meta-analysis of the effectiveness and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria. J Antimicrob Chemother 60:929–936

    Article  CAS  Google Scholar 

  153. Looareesuwan S, Chulay JD, Canfield CJ et al (1999) 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 60:533–541

    CAS  Google Scholar 

  154. Gregson A, Plowe CV (2005) Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57:117–145

    Article  CAS  Google Scholar 

  155. Sibley CH, Hyde JE, Sims PF et al (2001) Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol 17:582–588

    Article  CAS  Google Scholar 

  156. Cui L, Su XZ (2009) Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther 7:999–1013

    Article  CAS  Google Scholar 

  157. Wilson AL (2011) A systematic review and meta-analysis of the efficacy and safety of intermittent preventive treatment of malaria in children (IPTc). PLoS One 6:e16976

    Article  CAS  Google Scholar 

  158. Gosling RD, Carneiro I, Chandramohan D (2009) Intermittent preventive treatment of malaria in infants: how does it work and where will it work? Trop Med Int Health 14:1003–1010

    Article  CAS  Google Scholar 

  159. Briand V, Bottero J, Noel H et al (2009) Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine-pyrimethamine with mefloquine. J Infect Dis 200:991–1001

    Article  CAS  Google Scholar 

  160. Cisse B, Cairns M, Faye E et al (2009) Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children. PLoS One 4:e7164

    Article  CAS  Google Scholar 

  161. Hyde JE (2008) Antifolate resistance in Africa and the 164-dollar question. Trans R Soc Trop Med Hyg 102:301–303

    Article  Google Scholar 

  162. Nzila A, Ochong E, Nduati E et al (2005) Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet? Trans R Soc Trop Med Hyg 99:341–346

    Article  CAS  Google Scholar 

  163. Sridaran S, McClintock SK, Syphard LM et al (2010) Anti-folate drug resistance in Africa: meta-analysis of reported dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant genotype frequencies in African Plasmodium falciparum parasite populations. Malar J 9:247

    Article  Google Scholar 

  164. Nair S, Miller B, Barends M et al (2008) Adaptive copy number evolution in malaria parasites. PLoS Genet 4:e1000243

    Article  CAS  Google Scholar 

  165. Sandefur CI, Wooden JM, Quaye IK et al (2007) Pyrimethamine-resistant dihydrofolate reductase enzymes of Plasmodium falciparum are not enzymatically compromised in vitro. Mol Biochem Parasitol 154:1–5

    Article  CAS  Google Scholar 

  166. Sirawaraporn W, Sathitkul T, Sirawaraporn R et al (1997) Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc Natl Acad Sci USA 94:1124–1129

    Article  CAS  Google Scholar 

  167. Wootton JC, Feng X, Ferdig MT et al (2002) Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418:320–323

    Article  CAS  Google Scholar 

  168. Maiga O, Djimde AA, Hubert V et al (2007) A shared Asian origin of the triple-mutant dhfr allele in Plasmodium falciparum from sites across Africa. J Infect Dis 196:165–172

    Article  CAS  Google Scholar 

  169. McCollum AM, Basco LK, Tahar R et al (2008) Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistance alleles in a population from central Africa. Antimicrob Agents Chemother 52:4089–4097

    Article  CAS  Google Scholar 

  170. Mita T (2010) Origins and spread of pfdhfr mutant alleles in Plasmodium falciparum. Acta Trop 114:166–170

    Article  CAS  Google Scholar 

  171. Mita T, Tanabe K, Kita K (2009) Spread and evolution of Plasmodium falciparum drug resistance. Parasitol Int 58:201–209

    Article  CAS  Google Scholar 

  172. Roper C, Pearce R, Nair S et al (2004) Intercontinental spread of pyrimethamine-resistant malaria. Science 305:1124

    Article  CAS  Google Scholar 

  173. Certain LK, Briceno M, Kiara SM et al (2008) Characteristics of Plasmodium falciparum dhfr haplotypes that confer pyrimethamine resistance, Kilifi, Kenya, 1987–2006. J Infect Dis 197:1743–1751

    Article  Google Scholar 

  174. McCollum AM, Poe AC, Hamel M et al (2006) Antifolate resistance in Plasmodium falciparum: multiple origins and identification of novel dhfr alleles. J Infect Dis 194:189–197

    Article  CAS  Google Scholar 

  175. Pearce RJ, Pota H, Evehe MS et al (2009) Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria. PLoS Med 6:e1000055

    Article  CAS  Google Scholar 

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Acknowledgement

The authors thank the support of the University of Cape Town.

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Authors and Affiliations

  1. Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, 230, 80108, Kilifi, Kenya

    John Okombo & Leah Mwai

  2. Departments of Chemistry and Clinical Pharmacology, University of Cape Town, Rondebosch 7701, Cape Town, South Africa

    Alexis Nzila

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  1. John Okombo
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  2. Leah Mwai
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  1. , Dept. of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa

    Kelly Chibale

  2. , Department of Chemistry, Rhodes University, Grahamstown, 6140, South Africa

    Mike Davies-Coleman

  3. and Technology, African Institute of Biomedical Science, Harare, 2294, Zimbabwe

    Collen Masimirembwa

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Okombo, J., Mwai, L., Nzila, A. (2012). Tackling the Problem of Antimalarial Resistance. In: Chibale, K., Davies-Coleman, M., Masimirembwa, C. (eds) Drug Discovery in Africa. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28175-4_13

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