Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Review Article

An Overview of Available Antimalarials: Discovery, Mode of Action and Drug Resistance

Author(s): Yu-Qing Tang, Qian Ye, He Huang and Wei-Yi Zheng*

Volume 20, Issue 8, 2020

Page: [583 - 592] Pages: 10

DOI: 10.2174/1566524020666200207123253

Price: $65

Abstract

Malaria is one of the three most deadly infectious diseases in the world and seriously endangers human health and life. To reduce the public health burden of this disease, scientists have focused on the discovery and development of effective antimalarial drugs, from quinine and chloroquine to antifolates and artemisinin and its derivatives, which all play a profound role in the treatment of malaria. However, drugresistant strains of Plasmodium falciparum have emerged due to frequent use of antimalarials and have become increasingly resistant to existing antimalarial drugs, causing disastrous consequences in the world. In particular, artemisinin resistance is of greatest concern which was reported in 2008. Resistance to artenisinins has been a major obstacle for malaria control, and current efforts to curb artemisinin resistance have not been successful. Based on the current situation, it is urgent to develop more effective new antimalarials with distinct targets from conventional antimalarials in the world, which could facilitate to minimize the phenomenon of drug resistance. This review aims to summarize different kinds of antimalarial therapeutic efficacy, mechanisms of action and resistance, and proposes new solutions aiming towards further improvement of malaria elimination.

Keywords: Malaria, antimalarials, plasmodium falciparum, mechanism of action, drug resistance, artemisinin.

Next »
[1]
Diagana TT. Supporting malaria elimination with 21st century antimalarial agent drug discovery. Drug Discov Today 2015; 20(10): 1265-70.
[http://dx.doi.org/10.1016/j.drudis.2015.06.009] [PMID: 26103616]
[2]
Mphatswe W, Mate KS, Bennett B, et al. Improving public health information: a data quality intervention in KwaZulu-Natal, South Africa. Bull World Health Organ 2012; 90(3): 176-82.
[http://dx.doi.org/10.2471/BLT.11.092759] [PMID: 22461712]
[3]
Ouji M, Augereau JM, Paloque L, Benoit-Vical F. Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination. Parasite 2018; 25: 24.
[http://dx.doi.org/10.1051/parasite/2018021] [PMID: 29676250]
[4]
Shanks GD. Historical Review: Problematic Malaria Prophylaxis with Quinine. Am J Trop Med Hyg 2016; 95(2): 269-72.
[http://dx.doi.org/10.4269/ajtmh.16-0138] [PMID: 27185766]
[5]
Goss A. Building the world’s supply of quinine: Dutch colonialism and the origins of a global pharmaceutical industry. Endeavour 2014; 38(1): 8-18.
[http://dx.doi.org/10.1016/j.endeavour.2013.10.002] [PMID: 24287061]
[6]
Von Seidlein L, Dondorp A. Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance. Expert Rev Anti Infect Ther 2015; 13(6): 715-30.
[http://dx.doi.org/10.1586/14787210.2015.1031744] [PMID: 25831482]
[7]
Peters W. Antimalarial drug resistance: an increasing problem. Br Med Bull 1982; 38(2): 187-92.
[http://dx.doi.org/10.1093/oxfordjournals.bmb.a071757] [PMID: 7052200]
[8]
Karlsson KK, Hellgren U, Alván G, Rombo L. Audiometry as a possible indicator of quinine plasma concentration during treatment of malaria. Trans R Soc Trop Med Hyg 1990; 84(6): 765-7.
[http://dx.doi.org/10.1016/0035-9203 (90)90069-Q] [PMID: 2096500]
[9]
Kluska M, Marciniuk-Kluska A, Prukała D, Prukała W. Analytics of Quinine and its Derivatives. Crit Rev Anal Chem 2016; 46(2): 139-45.
[http://dx.doi.org/10.1080/10408347.2014.996700] [PMID: 25831406]
[10]
WHO. Malaria Treatment Guidelines 2010.
[11]
Tse EG, Korsik M, Todd MH. The past, present and future of anti-malarial medicines. Malar J 2019; 18(1): 93.
[http://dx.doi.org/10.1186/s12936-019-2724-z] [PMID: 30902052]
[12]
Thomé R, Lopes SC, Costa FT, Verinaud L. Chloroquine: modes of action of an undervalued drug. Immunol Lett 2013; 153(1-2): 50-7.
[http://dx.doi.org/10.1016/j.imlet.2013.07.004] [PMID: 23891850]
[13]
Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol 2012; 42(2): 145-53.
[http://dx.doi.org/10.1007/s12016-010-8243-x] [PMID: 21221847]
[14]
Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 2002; 298(5591): 210-3.
[http://dx.doi.org/10.1126/science.1074045] [PMID: 12364805]
[15]
Mushtaque M. Shahjahan. Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review. Eur J Med Chem 2015; 90: 280-95.
[http://dx.doi.org/10.1016/j.ejmech.2014.11.022] [PMID: 25461328]
[16]
Antony HA, Parija SC. Antimalarial drug resistance: An overview. Trop Parasitol 2016; 6(1): 30-41.
[http://dx.doi.org/10.4103/2229-5070.175081] [PMID: 26998432]
[17]
Baird JK, Hoffman SL. Primaquine therapy for malaria. Clin Infect Dis 2004; 39(9): 1336-45.
[http://dx.doi.org/10.1086/424663] [PMID: 15494911]
[18]
Thomas D, Tazerouni H, Sundararaj KG, Cooper JC. Therapeutic failure of primaquine and need for new medicines in radical cure of Plasmodium vivax. Acta Trop 2016; 160: 35-8.
[http://dx.doi.org/10.1016/j.actatropica.2016.04.009] [PMID: 27109040]
[19]
Buchachart K, Krudsood S, Singhasivanon P, et al. Effect of primaquine standard dose (15 mg/day for 14 days) in the treatment of vivax malaria patients in Thailand. Southeast Asian J Trop Med Public Health 2001; 32(4): 720-6.
[PMID: 12041544]
[20]
Burrows JN, Burlot E, Campo B. Antimalarial drug discovery-the path towards eradication. Parasitology 2014; 141(1): 1-12.
[http://dx.doi.org/10.1017/S0031182013000826] [PMID: 24401336]
[21]
Ashley EA, Recht J, White NJ. Primaquine: the risks and the benefits. Malar J 2014; 13: 418.
[http://dx.doi.org/10.1186/1475-2875-13-418] [PMID: 25363455]
[22]
Abdul-Ghani R, Farag HF, Allam AF. Sulfadoxine-pyrimethamine resistance in Plasmodium falciparum: a zoomed image at the molecular level within a geographic context. Acta Trop 2013; 125(2): 163-90.
[http://dx.doi.org/10.1016/j.actatropica.2012.10.013] [PMID: 23131424]
[23]
Richards WH. Antimalarial activity of sulphonamides and a sulphone, singly and in combination with pyrimethamine, against drug resistant and normal strains of laboratory plasmodia. Nature 1966; 212(5069): 1494-5.
[http://dx.doi.org/10.1038/2121494a0] [PMID: 21090431]
[24]
White NJ. Antimalarial drug resistance. J Clin Invest 2004; 113(8): 1084-92.
[http://dx.doi.org/10.1172/JCI21682] [PMID: 15085184]
[25]
White NJ. Antimalarial drug resistance: the pace quickens. J Antimicrob Chemother 1992; 30(5): 571-85.
[http://dx.doi.org/10.1093/jac/30.5.571] [PMID: 1493976]
[26]
Verdrager J. Epidemiology of the emergence and spread of drug-resistant falciparum malaria in South-East Asia and Australasia. J Trop Med Hyg 1986; 89(6): 277-89.
[PMID: 3543384]
[27]
Warhurst DC. Resistance to antifolates in Plasmodium falciparum, the causative agent of tropical malaria. Sci Prog 2002; 85(Pt 1): 89-111.
[http://dx.doi.org/10.3184/003685002783238906] [PMID: 11969121]
[28]
Li Y. Qinghaosu (artemisinin): chemistry and pharmacology. Acta Pharmacol Sin 2012; 33(9): 1141-6.
[http://dx.doi.org/10.1038/aps.2012.104] [PMID: 22922345]
[29]
Mei L, Shi K, Su J, Zha Z, Liu L. Progress in domestic study of artemisinin. J Laser 2008; 29(2): 95-6.
[30]
O’Neill PM, Posner GH. A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem 2004; 47(12): 2945-64.
[http://dx.doi.org/10.1021/jm030571c] [PMID: 15163175]
[31]
WHO. World malaria report 2017.
[32]
WHO. Status report on artemisinin and ACT resistance 2017.
[33]
Ruocco V, Ruocco E, Schwartz RA, Janniger CK. Kaposi sarcoma and quinine: a potentially overlooked triggering factor in millions of Africans. J Am Acad Dermatol 2011; 64(2): 434-6.
[http://dx.doi.org/10.1016/j.jaad.2009.12.016] [PMID: 21238829]
[34]
Lehane AM, McDevitt CA, Kirk K, Fidock DA. Degrees of chloroquine resistance in Plasmodium - is the redox system involved? Int J Parasitol Drugs Drug Resist 2012; 2: 47-57.
[http://dx.doi.org/10.1016/j.ijpddr.2011.11.001] [PMID: 22773965]
[35]
Sullivan DJ Jr, Gluzman IY, Russell DG, Goldberg DE. On the molecular mechanism of chloroquine’s antimalarial action. Proc Natl Acad Sci USA 1996; 93(21): 11865-70.
[http://dx.doi.org/10.1073/pnas.93.21.11865] [PMID: 8876229]
[36]
Fitch CD. Chloroquine resistance in malaria: a deficiency of chloroquine binding. Proc Natl Acad Sci USA 1969; 64(4): 1181-7.
[http://dx.doi.org/10.1073/pnas.64.4.1181] [PMID: 5271747]
[37]
Bitonti AJ, Sjoerdsma A, McCann PP, et al. Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine. Science 1988; 242(4883): 1301-3.
[http://dx.doi.org/10.1126/science.3057629] [PMID: 3057629]
[38]
Krogstad DJ, Gluzman IY, Kyle DE, et al. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 1987; 238(4831): 1283-5.
[http://dx.doi.org/10.1126/science.3317830] [PMID: 3317830]
[39]
Fidock DA, Nomura T, Talley AK, 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.
[http://dx.doi.org/10.1016/S1097-2765(05)00077-8] [PMID: 11090624]
[40]
Lakshmanan V, Bray PG, Verdier-Pinard D, et al. A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J 2005; 24(13): 2294-305.
[http://dx.doi.org/10.1038/sj.emboj.7600681] [PMID: 15944738]
[41]
Foote SJ, Thompson JK, Cowman AF, Kemp DJ. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 1989; 57(6): 921-30.
[http://dx.doi.org/10.1016/0092-8674 (89)90330-9] [PMID: 2701941]
[42]
Wilson CM, Serrano AE, Wasley A, Bogenschutz MP, Shankar AH, Wirth DF. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 1989; 244(4909): 1184-6.
[http://dx.doi.org/10.1126/science.2658061] [PMID: 2658061]
[43]
Djimdé A, Doumbo OK, Cortese JF, et al. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 2001; 344(4): 257-63.
[http://dx.doi.org/10.1056/NEJM200101253440403] [PMID: 11172152]
[44]
van Es HH, Karcz S, Chu F, et al. Expression of the plasmodial pfmdr1 gene in mammalian cells is associated with increased susceptibility to chloroquine. Mol Cell Biol 1994; 14(4): 2419-28.
[http://dx.doi.org/10.1128/MCB.14.4.2419] [PMID: 7511206]
[45]
Mbacham WF, Evehe MSB, Netongo PM, et al. Mutations within folate metabolising genes of Plasmodium falciparum in Cameroon. Afr J Biotechnol 2009; 8(19): 4749-54.
[46]
WHO. A strategic framework for malaria control and prevention during pregnancy in the African region. Brazzaville 2004.
[47]
Lumb V, Das MK, Singh N, Dev V, Khan W, Sharma YD. Multiple origins of Plasmodium falciparum dihydropteroate synthetase mutant alleles associated with sulfadoxine resistance in India. Antimicrob Agents Chemother 2011; 55(6): 2813-7.
[http://dx.doi.org/10.1128/AAC.01151-10] [PMID: 21422213]
[48]
Yuthavong Y. Basis for antifolate action and resistance in malaria. Microbes Infect 2002; 4(2): 175-82.
[http://dx.doi.org/10.1016/S1286-4579 (01)01525-8] [PMID: 11880049]
[49]
Cowman AF, Morry MJ, Biggs BA, Cross GA, Foote SJ. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 1988; 85(23): 9109-13.
[http://dx.doi.org/10.1073/pnas.85.23.9109] [PMID: 3057499]
[50]
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 USA 1988; 85(23): 9114-8.
[http://dx.doi.org/10.1073/pnas.85.23.9114] [PMID: 2904149]
[51]
Cowman AF. Mechanisms of drug resistance in malaria. Aust N Z J Med 1995; 25(6): 837-44.
[http://dx.doi.org/10.1111/j.1445-5994.1995.tb02889.x] [PMID: 8770361]
[52]
Sibley CH, Hyde JE, Sims PF, et al. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol 2001; 17(12): 582-8.
[http://dx.doi.org/10.1016/S1471-4922 (01)02085-2] [PMID: 11756042]
[53]
Kublin JG, Dzinjalamala FK, Kamwendo DD, 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.
[http://dx.doi.org/10.1086/338566] [PMID: 11807721]
[54]
Triglia T, Wang P, Sims PF, Hyde JE, Cowman AF. 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.
[http://dx.doi.org/10.1093/emboj/17.14.3807] [PMID: 9669998]
[55]
Dai YF, Zhou WW, Meng J, et al. The pharmacological activities and mechanisms of artemisinin and its derivatives: a systematic review. Med Chem Res 2017; 26(5): 867-80.
[http://dx.doi.org/10.1007/s00044-016-1778-5]
[56]
Meunier B, Robert A. Heme as trigger and target for trioxane-containing antimalarial drugs. Acc Chem Res 2010; 43(11): 1444-51.
[http://dx.doi.org/10.1021/ar100070k] [PMID: 20804120]
[57]
Meshnick SR, Thomas A, Ranz A, Xu CM, Pan HZ. Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action. Mol Biochem Parasitol 1991; 49(2): 181-9.
[http://dx.doi.org/10.1016/0166-6851(91)90062-B] [PMID: 1775162]
[58]
Kannan R, Sahal D, Chauhan VS. Heme-artemisinin adducts are crucial mediators of the ability of artemisinin to inhibit heme polymerization. Chem Biol 2002; 9(3): 321-32.
[http://dx.doi.org/10.1016/S1074-5521(02)00117-5] [PMID: 11927257]
[59]
Li J, Zhou B. Biological actions of artemisinin: insights from medicinal chemistry studies. Molecules 2010; 15(3): 1378-97.
[http://dx.doi.org/10.3390/molecules15031378] [PMID: 20335987]
[60]
del Pilar Crespo M, Avery TD, Hanssen E, 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.
[http://dx.doi.org/10.1128/AAC.00609-07] [PMID: 17938190]
[61]
Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 2002; 32(13): 1655-60.
[http://dx.doi.org/10.1016/S0020-7519 (02)00194-7] [PMID: 12435450]
[62]
O’Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin--the debate continues. Molecules 2010; 15(3): 1705-21.
[http://dx.doi.org/10.3390/molecules15031705] [PMID: 20336009]
[63]
Klonis N, Crespo-Ortiz MP, Bottova I, et al. Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci USA 2011; 108(28): 11405-10.
[http://dx.doi.org/10.1073/pnas.1104063108] [PMID: 21709259]
[64]
Cui L, Su XZ. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther 2009; 7(8): 999-1013.
[http://dx.doi.org/10.1586/eri.09.68] [PMID: 19803708]
[65]
Mok S, Ashley EA, Ferreira PE, et al. Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science 2015; 347(6220): 431-5.
[http://dx.doi.org/10.1126/science.1260403] [PMID: 25502316]
[66]
Dogovski C, Xie SC, Burgio G, et al. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol 2015; 13(4)e1002132
[http://dx.doi.org/10.1371/journal.pbio.1002132] [PMID: 25901609]
[67]
Ghorbal M, Gorman M, Macpherson CR, Martins RM, Scherf A, Lopez-Rubio JJ. Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system. Nat Biotechnol 2014; 32(8): 819-21.
[http://dx.doi.org/10.1038/nbt.2925] [PMID: 24880488]
[68]
Straimer J, Gnädig NF, Witkowski B, et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 2015; 347(6220): 428-31.
[http://dx.doi.org/10.1126/science.1260867] [PMID: 25502314]
[69]
Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 2014; 505(7481): 50-5.
[http://dx.doi.org/10.1038/nature12876] [PMID: 24352242]
[70]
Adams J, Kelso R, Cooley L. The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol 2000; 10(1): 17-24.
[http://dx.doi.org/10.1016/S0962-8924(99)01673-6] [PMID: 10603472]
[71]
Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 2004; 24(24): 10941-53.
[http://dx.doi.org/10.1128/MCB.24.24.10941-10953.2004] [PMID: 15572695]
[72]
Suresh N, Haldar K. Mechanisms of artemisinin resistance in Plasmodium falciparum malaria. Curr Opin Pharmacol 2018; 42: 46-54.
[http://dx.doi.org/10.1016/j.coph.2018.06.003] [PMID: 30077118]
[73]
Van Y, Chotivanich K, Nguon C, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature 2015; 520(7549): 683-7.
[74]
Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 359(24): 2619-20.
[http://dx.doi.org/10.1056/NEJMc0805011] [PMID: 19064625]
[75]
Denis MB, Tsuyuoka R, Poravuth Y, et al. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health 2006; 11(9): 1360-6.
[http://dx.doi.org/10.1111/j.1365-3156.2006.01690.x] [PMID: 16930257]
[76]
Saunders DL, Vanachayangkul P, Lon C US. Army Military Malaria Research Program; National Center for Parasitology, Entomology, and Malaria Control (CNM); Royal Cambodian Armed Forces. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med 2014; 371(5): 484-5.
[http://dx.doi.org/10.1056/NEJMc1403007] [PMID: 25075853]
[77]
White NJ. Counter perspective: artemisinin resistance: facts, fears, and fables. Am J Trop Med Hyg 2012; 87(5): 785.
[http://dx.doi.org/10.4269/ajtmh.2012.12-0573] [PMID: 23136172]
[78]
Leang R, Barrette A, Bouth DM, et al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrob Agents Chemother 2013; 57(2): 818-26.
[http://dx.doi.org/10.1128/AAC.00686-12] [PMID: 23208711]
[79]
Cui L, Mharakurwa S, Ndiaye D, Rathod PK, Rosenthal PJ. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network. Am J Trop Med Hyg 2015; 93(3)(Suppl.): 57-68.
[http://dx.doi.org/10.4269/ajtmh.15-0007] [PMID: 26259943]
[80]
Blasco B, Leroy D, Fidock DA. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nat Med 2017; 23(8): 917-28.
[http://dx.doi.org/10.1038/nm.4381] [PMID: 28777791]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy