Abstract
One of the greatest obstacles to the control of malaria has been the spread of resistance to drugs used on a large scale. This review provides an update of the current understanding of the molecular basis for antimalarial drug resistance. Parasite intrinsic resistance is just one component that determines the in vivo efficacy of a drug. Human immune responses and pharmacologic properties play important roles in determining the clinical outcome of treatment. The emergence and spread of resistance also results from an interplay of these factors. Current efforts to characterize and deter resistance to new combination therapy are also discussed.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ACT:
-
artemisinin-based combination therapy
- DHFR:
-
dihydrofolate reductase
- DHPS:
-
dihydropteroate synthetase
- PfCRT:
-
Plasmodium falciparum chloroquine-resistance transporter
- PfMDR:
-
Plasmodium falciparum multidrug resistance gene
- SP:
-
sulfadoxine-pyrimethamine
- WHO:
-
World Health Organization
References
World Health Organization 2008 World Malaria Report 2008.
Trape JF, Legros F, Ndiaye P, Konate L, Bah IB, Diallo S, Verdier F, Hatin I, Le Bras J 1989 Chloroquine-resistant Plasmodium falciparum malaria in Senegal. Trans R Soc Trop Med Hyg 83: 761
Zucker JR, Ruebush TK, Obonyo C, Otieno J, Campbell CC 2003 The mortality consequences of the continued use of chloroquine in Africa: experience in Siaya, western Kenya. Am J Trop Med Hyg 68: 386–390
Sibley CH, Hyde JE, Sims PF, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM 2001 Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next?. Trends Parasitol 17: 582–588
Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR 2002 Epidemiology of drug-resistant malaria. Lancet Infect Dis 2: 209–218
Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, O'Neill PM, Bray PG, Ward SA, Krishna S 2003 Artemisinins target the SERCA of Plasmodium falciparum. Nature 424: 957–961
ter Kuile F, White NJ, Holloway P, Pasvol G, Krishna S 1993 Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Exp Parasitol 76: 85–95
White NJ 2008 Qinghaosu (artemisinin): the price of success. Science 320: 330–334
Pukrittayakamee S, Chotivanich K, Chantra A, Clemens R, Looareesuwan S, White NJ 2004 Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother 48: 1329–1334
Ittarat W, Pickard AL, Rattanasinganchan P, Wilairatana P, Looareesuwan S, Emery K, Low J, Udomsangpetch R, Meshnick SR 2003 Recrudescence in artesunate-treated patients with falciparum malaria is dependent on parasite burden not on parasite factors. Am J Trop Med Hyg 68: 147–152
Wellems TE, Walker-Jonah A, Panton LJ 1991 Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc Natl Acad Sci USA 88: 3382–3386
Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LM, Sidhu AB, Naude B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE 2000 Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6: 861–871
Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte Y, Dicko A, Su XZ, Nomura T, Fidock DA, Wellems TE, Plowe CV, Coulibaly D 2001 A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257–263
Durand R, Jafari S, Vauzelle J, Delabre JF, Jesic Z, Le Bras J 2001 Analysis of pfcrt point mutations and chloroquine susceptibility in isolates of Plasmodium falciparum. Mol Biochem Parasitol 114: 95–102
Lakshmanan V, Bray PG, Verdier-Pinard D, Johnson DJ, Horrocks P, Muhle RA, Alakpa GE, Hughes RH, Ward SA, Krogstad DJ, Sidhu AB, Fidock DA 2005 A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J 24: 2294–2305
Valderramos SG, Fidock DA 2006 Transporters involved in resistance to antimalarial drugs. Trends Pharmacol Sci 27: 594–601
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
Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, Winstanley PA, Estrada-Franco JG, Mollinedo RE, Avila JC, Cespedes JL, Carter D, Doumbo OK 1997 Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J Infect Dis 176: 1590–1596
Gregson A, Plowe CV 2005 Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57: 117–145
Ter Kuile FO, van Eijk AM, Filler SJ 2007 Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review. JAMA 297: 2603–2616
Nzila A, Ochong E, Nduati E, Gilbert K, Winstanley P, Ward S, Marsh K 2005 Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet?. Trans R Soc Trop Med Hyg 99: 341–346
Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, Magill AJ, Su XZ 2002 Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418: 320–323
Wellems TE, Plowe CV 2001 Chloroquine-resistant malaria. J Infect Dis 184: 770–776
Clyde DF 1954 Observations on monthly pyrimethamine (daraprim) prophylaxis in an East African village. East Afr Med J 31: 41–46
Maiga O, Djimde AA, Hubert V, Renard E, Aubouy A, Kironde F, Nsimba B, Koram K, Doumbo OK, Le Bras J, Clain J 2007 A shared Asian origin of the triple-mutant dhfr allele in Plasmodium falciparum from sites across Africa. J Infect Dis 196: 165–172
Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T 2004 Intercontinental spread of pyrimethamine-resistant malaria. Science 305: 1124
Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, Djimde AA, Kouriba B, Taylor TE, Plowe CV 2003 Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 187: 1870–1875
Nkhoma S, Molyneux M, Ward S 2007 Molecular surveillance for drug-resistant Plasmodium falciparum malaria in Malawi. Acta Trop 102: 138–142
Laufer MK, Thesing PC, Eddington ND, Masonga R, Dzinjalamala FK, Takala SL, Taylor TE, Plowe CV 2006 Return of chloroquine antimalarial efficacy in Malawi. N Engl J Med 355: 1959–1966
Rohrbach P, Sanchez CP, Hayton K, Friedrich O, Patel J, Sidhu AB, Ferdig MT, Fidock DA, Lanzer M 2006 Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. EMBO J 25: 3000–3011
Duah NO, Wilson MD, Ghansah A, Abuaku B, Edoh D, Quashie NB, Koram KA 2007 Mutations in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance genes, and treatment outcomes in Ghanaian children with uncomplicated malaria. J Trop Pediatr 53: 27–31
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
Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Bjorkman A, Gil JP 2005 In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis 191: 1014–1017
Alker AP, Lim P, Sem R, Shah NK, Yi P, Bouth DM, Tsuyuoka R, Maguire JD, Fandeur T, Ariey F, Wongsrichanalai C, Meshnick SR 2007 Pfmdr1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border. Am J Trop Med Hyg 76: 641–647
Price RN, Uhlemann AC, van Vugt M, Brockman A, Hutagalung R, Nair S, Nash D, Singhasivanon P, Anderson TJ, Krishna S, White NJ, Nosten F 2006 Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis 42: 1570–1577
Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, Patel R, Laing K, Looareesuwan S, White NJ, Nosten F, Krishna S 2004 Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364: 438–447
Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock DA 2006 Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis 194: 528–535
Nair S, Miller B, Barends M, Jaidee A, Patel J, Mayxay M, Newton P, Nosten F, Ferdig MT, Anderson TJ 2008 Adaptive copy number evolution in malaria parasites. PLoS Genet 4: e1000243
Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, Ekala MT, Bouchier C, Esterre P, Fandeur T, Mercereau-Puijalon O 2005 Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 366: 1960–1963
Zhang G, Guan Y, Zheng B, Wu S, Tang L 2008 No PfATPase6 S769N mutation found in Plasmodium falciparum isolates from China. Malar J 7: 122
Mugittu K, Genton B, Mshinda H, Beck HP 2006 Molecular monitoring of Plasmodium falciparum resistance to artemisinin in Tanzania. Malar J 5: 126
Ferreira ID, Lopes D, Martinelli A, Ferreira C, Do Rosario VE, Cravo P 2007 In vitro assessment of artesunate, artemether and amodiaquine susceptibility and molecular analysis of putative resistance-associated mutations of Plasmodium falciparum from Sao Tome and Principe. Trop Med Int Health 12: 353–362
Stepniewska K, White NJ 2008 Pharmacokinetic determinants of the window of selection for antimalarial drug resistance. Antimicrob Agents Chemother 52: 1589–1596
Nyunt MM, Plowe CV 2007 Pharmacologic advances in the global control and treatment of malaria: combination therapy and resistance. Clin Pharmacol Ther 82: 601–605
Watkins WM, Mosobo M 1993 Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life. Trans R Soc Trop Med Hyg 87: 75–78
Hastings IM, Ward SA 2005 Coartem (artemether-lumefantrine) in Africa: the beginning of the end?. J Infect Dis 192: 1303–1304
Djimde AA, Fofana B, Sagara I, Sidibe B, Toure S, Dembele D, Dama S, Ouologuem D, Dicko A, Doumbo OK 2008 Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali. Am J Trop Med Hyg 78: 455–461
Holmgren G, Gil JP, Ferreira PM, Veiga MI, Obonyo CO, Bjorkman A 2006 Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infect Genet Evol 6: 309–314
Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Bjorkman A 2005 Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis 41: 1079–1086
Barnes KI, Lindegardh N, Ogundahunsi O, Olliaro P, Plowe CV, Randrianarivelojosia M, Gbotosho GO, Watkins WM, Sibley CH, White NJ 2007 World Antimalarial Resistance Network (WARN) IV: clinical pharmacology. Malar J 6: 122
White NJ, Stepniewska K, Barnes K, Price RN, Simpson J 2008 Simplified antimalarial therapeutic monitoring: using the day-7 drug level?. Trends Parasitol 24: 159–163
Barnes KI, Watkins WM, White NJ 2008 Antimalarial dosing regimens and drug resistance. Trends Parasitol 24: 127–134
Simpson JA, Watkins ER, Price RN, Aarons L, Kyle DE, White NJ 2000 Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob Agents Chemother 44: 3414–3424
Kofoed PE, Lopez F, Johansson P, Sandstrom A, Hedegaard K, Aaby P, Rombo L 2002 Treatment of children with Plasmodium falciparum malaria with chloroquine in Guinea-Bissau. Am J Trop Med Hyg 67: 28–31
Ursing J, Schmidt BA, Lebbad M, Kofoed PE, Dias F, Gil JP, Rombo L 2007 Chloroquine resistant P. falciparum prevalence is low and unchanged between 1990 and 2005 in Guinea-Bissau: an effect of high chloroquine dosage?. Infect Genet Evol 7: 555–561
Newton PN, Fernandez FM, Plancon A, Mildenhall DC, Green MD, Ziyong L, Christophel EM, Phanouvong S, Howells S, McIntosh E, Laurin P, Blum N, Hampton CY, Faure K, Nyadong L, Soong CW, Santoso B, Zhiguang W, Newton J, Palmer K 2008 A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Med 5: e32
Atemnkeng MA, De Cock K, Plaizier-Vercammen J 2007 Quality control of active ingredients in artemisinin-derivative antimalarials within Kenya and DR Congo. Trop Med Int Health 12: 68–74
Bate R, Coticelli P, Tren R, Attaran 2008 A Antimalarial drug quality in the most severely malarious parts of Africa-a six country study. PLoS ONE 3: e2132
Hastings IM 2006 Complex dynamics and stability of resistance to antimalarial drugs. Parasitology 132: 615–624
Djimde AA, Doumbo OK, Traore O, Guindo AB, Kayentao K, Diourte Y, Niare-Doumbo S, Coulibaly D, Kone AK, Cissoko Y, Tekete M, Fofana B, Dicko A, Diallo DA, Wellems TE, Kwiatkowski D, Plowe CV 2003 Clearance of drug-resistant parasites as a model for protective immunity in Plasmodium falciparum malaria 1. Am J Trop Med Hyg 69: 558–563
Laufer MK, van Oosterhout JJ, Thesing PC, Dzinjalamala FK, Hsi T, Beraho L, Graham SM, Taylor TE, Plowe CV 2007 Malaria treatment efficacy among people living with HIV: the role of host and parasite factors. Am J Trop Med Hyg 77: 627–632
Hoffman SL, Masbar S, Hussein PR, Soewarta A, Harun S, Marwoto HA, Campbell JR, Smrkovski L, Purnomo Wiady I 1984 Absence of malaria mortality in villagers with chloroquine-resistant Plasmodium falciparum treated with chloroquine. Trans R Soc Trop Med Hyg 78: 175–178
Min-Oo G, Gros P 2005 Erythrocyte variants and the nature of their malaria protective effect 6. Cell Microbiol 7: 753–763
Ittarat W, Looareesuwan S, Pootrakul P, Sumpunsirikul P, Vattanavibool P, Meshnick SR 1998 Effects of alpha-thalassemia on pharmacokinetics of the antimalarial agent artesunate. Antimicrob Agents Chemother 42: 2332–2335
Kamchonwongpaisan S, Chandra-ngam G, Avery MA, Yuthavong Y 1994 Resistance to artemisinin of malaria parasites (Plasmodium falciparum) infecting alpha-thalassemic erythrocytes in vitro. Competition in drug accumulation with uninfected erythrocytes 1. J Clin Invest 93: 467–473
Mockenhaupt FP, May J, Bergqvist Y, Meyer CG, Falusi AG, Bienzle U 2001 Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children. Trop Med Int Health 6: 102–107
Laufer MK, Plowe CV 2007 The Interaction between HIV and malaria in Africa. Curr Infect Dis Rep 9: 47–54
Van Geertruyden JP, Menten J, Colebunders R, Korenromp E, D'Alessandro U 2008 The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance. Malar J 7: 134
Denis MB, Tsuyuoka R, Poravuth Y, Narann TS, Seila S, Lim C, Incardona S, Lim P, Sem R, Socheat D, Christophel EM, Ringwald P 2006 Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health 11: 1360–1366
Vijaykadga S, Rojanawatsirivej C, Cholpol S, Phoungmanee D, Nakavej A, Wongsrichanalai C 2006 In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health 11: 211–219
Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM 2008 Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 359: 2619–2620
Sibley CH, Barnes KI, Watkins WM, Plowe CV 2008 A network to monitor antimalarial drug resistance: a plan for moving forward. Trends Parasitol 24: 43–48
Acknowledgements
We are grateful to Chris Plowe for his helpful comments.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by NIAID/NIH (M.A.T.), NIAID/NIH, Doris Duke Charitable Foundation and Pfizer (M.K.L.).
Rights and permissions
About this article
Cite this article
Travassos, M., Laufer, M. Resistance to Antimalarial Drugs: Molecular, Pharmacologic, and Clinical Considerations. Pediatr Res 65, 64–70 (2009). https://doi.org/10.1203/PDR.0b013e3181a0977e
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e3181a0977e
This article is cited by
-
Evaluation of the antimalarial activity and toxicity of Mahanil-Tang-Thong formulation and its plant ingredients
BMC Complementary Medicine and Therapies (2022)
-
Evaluation of the paediatric dose of chloroquine in the treatment of Plasmodium vivax malaria
Malaria Journal (2016)
-
Use of proscribed chloroquine is associated with an increased risk of pfcrt T76 mutation in some parts of Ghana
Malaria Journal (2014)
-
Methyl-methoxylpyrrolinone and flavinium nucleus binding signatures on falcipain-2 active site
Journal of Molecular Modeling (2014)
-
Open-label trial with artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria three years after its broad introduction in Jimma Zone, Ethiopia
Malaria Journal (2012)
