Molecular mechanisms of resistance in antimalarial chemotherapy: The unmet challenge

Annual Review of Pharmacology and Toxicology

Volumn 45, Issue , 2005, Pages 565-585

  Arav Boger, Ravit ^a   Shapiro, Theresa A ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Drug resistance; Malaria; Mutations; Plasmodium

Indexed keywords

ABC TRANSPORTER; ANTIMALARIAL AGENT; ARTEMISIN; ARTESUNATE; ATOVAQUONE; ATOVAQUONE PLUS PROGUANIL; AZITHROMYCIN; CHLORAMPHENICOL; CHLOROQUINE; CLINDAMYCIN; CYCLOGUANIL; FANSIDAR; FOLIC ACID; FOLIC ACID ANTAGONIST; FOSMIDOMYCIN; GLYCOPROTEIN P; HALOFANTRINE; IMIDAZOLE DERIVATIVE; MEFLOQUINE; MULTIDRUG RESISTANCE PROTEIN 1; PIPERAQUINE; PROGUANIL; PYRIMETHAMINE; QUININE; QUINOLINE DERIVATIVE; QUINOLINE DERIVED ANTIINFECTIVE AGENT; SULFADOXINE; SULFONAMIDE; UNINDEXED DRUG; VERAPAMIL;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ADULT; CHILD; DRUG COST; DRUG EFFICACY; DRUG SAFETY; ELECTRON TRANSPORT; GENE; GENE MUTATION; HUMAN; LIFE CYCLE; MALARIA; MALARIA CONTROL; MITOCHONDRION; MULTIDRUG RESISTANCE; NONHUMAN; OPPORTUNISTIC INFECTION; PARASITE; PFCRT GENE; PFMDR1 GENE; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PNEUMOCYSTIS PNEUMONIA; POINT MUTATION; PRIORITY JOURNAL; REVIEW;

ANIMALS; ANTIMALARIALS; DRUG DELIVERY SYSTEMS; DRUG RESISTANCE; HUMANS; MALARIA;

ARTESUNATE; CINCHONA PUBESCENS; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PNEUMOCYSTIS; PROTOZOA;

EID: 13844319811     PISSN: 03621642     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.45.120403.095946     Document Type: Review

References (134)

1. Krogstad DJ. 2000. Plasmodium species (Malaria). See Ref. 133, pp. 2818-32
2. Nchinda TC. 1998. Malaria: a reemerging disease in Africa. Emerg. Infect. Dis. 4:398-403
3. Wellems TE, Miller LH. 2003. Two worlds of malaria. N. Engl. J. Med. 349: 1496-98
4. Gardner MJ, Hall N, Fung E, White O, Berriman M, et al. 2002. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498-511
5. White NJ. 2004. Antimalarial drug resistance. J. Clin. Invest. 113:1084-92
6. Talisuna AO, Bloland P, d'Alessandro U. 2004. History, dynamics, and public health importance of malaria parasite resistance. Clin. Microbiol. Rev. 17:235-54
7. Rosenthal PJ. 2003. Antimalarial drug discovery: old and new approaches. J. Exp. Biol. 206:3735-44
8. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. 2002. Epidemiology of drug-resistant malaria. Lancet Infect. Dis. 2:209-18
9. Hyde JE. 2002. Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs. Microbes. Infect. 4:165-74
10. Winstanley P. 2001. Modern chemotherapeutic options for malaria. Lancet Infect. Dis. 1:242-50
11. Olliaro P. 2001. Mode of action and mechanisms of resistance for antimalarial drugs. Pharmacol Ther. 89:207-19
12. Warhurst D. 2001. New developments: chloroquine-resistance in Plasmodium falciparum. Drug Resist. Updat. 4:141-44
13. Peters W. 1987. Chemotherapy and Drug Resistance in Malaria. London: Academic Press
14. World Health Organization. 1973. Chemotherapy of malaria and resistance to antimalarials. WHO Tech. Rep. Ser. 529:1-121
15. Decuypere S, Elinck E, Van Overmeir C, Talisuna AO, d'Alessandro U, et al. 2003. Pathogen genotyping in polyclonal infections: application of a fluorogenic polymerase-chain-reaction assay in malaria. J. Infect. Dis. 188:1245-49
16. Opal SM, Mayer KH, Medeiros AA. 2000. Mechanisms of bacterial antibiotic resistance. See Ref. 133, pp. 236-53
17. Morrow CS, Cowan KH. 1997. Drug resistance and its clinical circumvention. In Cancer Medicine, ed. JF Holland, pp. 799-816. Baltimore: Williams & Wilkins
18. Hastings IM, Bray PG, Ward SA. 2002. Parasitology. A requiem for chloroquine. Science 298:74-75
19. Coatney RG. 1963. Pitfalls in a discovery: the chronicle of chloroquine. Am. J. Trop. Med. Hyg. 12:121-29
20. Greenwood BM, Bradley AK, Greenwood AM, Byass P, Jammeh K, et al. 1987. Mortality and morbidity from malaria among children in a rural area of The Gambia, West Africa. Trans. R. Soc. Trop. Med. Hyg. 81:478-86
21. Trape JF. 2001. The public health impact of chloroquine resistance in Africa. Am. J. Trop. Med. Hyg. 64:12-17
22. Trape JF, Pison G, Preziosi MP, Enel C, du Desgrees LA, et al. 1998. Impact of chloroquine resistance on malaria mortality. C. R. Acad. Sci. III 321:689-97
23. Francis SE, Sullivan DJ Jr, Goldberg DE. 1997. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu. Rev. Microbiol. 51:97-123
24. Thurston JP. 1951. Morphological changes in Plasmodium berghei following proguanil, sulphadiazine and mepacrine therapy. Trans. R. Soc. Trop. Med. Hyg. 44:703-6
25. Sullivan DJ Jr, Gluzman IY, Russell DG, Goldberg DE. 1996. On the molecular mechanism of chloroquine's antimalarial action. Proc. Natl. Acad. Sci. USA 93:11865-70
26. Macomber PB, O'Brien RL, Hahn FE. 1966. Chloroquine: physiological basis of drug resistance in Plasmodium berghei. Science 152:1374-75
27. Geary TG, Jensen JB. 1983. Lack of cross-resistance to 4-aminoquinolines in chloroquine-resistant Plasmodium falciparum in vitro. J. Parasitol. 69:97-105
28. Geary TG, Divo AA, Jensen JB. 1987. Activity of quinoline-containing antimalarials against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. Trans. R. Soc. Trop. Med. Hyg. 81:499-503
29. Krogstad DJ, Gluzman IY, Kyle DE, Oduola AM, Martin SK, et al. 1987. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238:1283-85
30. Martin SK, Oduola AM, Milhous WK. 1987. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235:899-901
31. Wellems TE, Panton LJ, Gluzman IY, do Rosario V, Gwadz RW, et al. 1990. Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345:253-55
32. Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, et al. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6:861-71
33. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. 2003. P-glycoprotein: from genomics to mechanism. Oncogene 22:7468-85
34. Borst P, Elferink RO. 2002. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71:537-92
35. Waller KL, Muhle RA, Ursos LM, Horrocks P, Verdier-Pinard D, et al. 2003. Chloroquine resistance modulated in vitro by expression levels of the Plasmodium falciparum chloroquine resistance transporter. J. Biol. Chem. 278:33593-601
36. Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, et al. 2001. A molecular marker for chloroquine-resistant falciparum malaria. N. Engl. J. Med. 344:257-63
37. Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, et al. 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418:320-23
38. Sidhu AB, Verdier-Pinard D, Fidock DA. 2002. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298:210-13
39. Cooper RA, Ferdig MT, Su XZ, Ursos LM, Mu J, et al. 2002. Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum. Mol. Pharmacol. 61:35-42
40. Wilson CM, Serrano AE, Wasley A, Bogenschutz MP, Shankar AH, Wirth DF. 1989. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 244:1184-86
41. Foote SJ, Thompson JK, Cowman AF, Kemp DJ. 1989. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 57:921-30
42. Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF. 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403:906-9
43. Rieckmann KH, Davis DR, Hutton DC. 1989. Plasmodium vivax resistance to chloroquine? Lancet 2:1183-84
44. Nomura T, Carlton JM, Baird JK, del Portillo HA, Fryauff DJ, et al. 2001. Evidence for different mechanisms of chloroquine resistance in 2 Plasmodium species that cause human malaria. J. Infect. Dis. 183:1653-61
45. De D, Krogstad FM, Byers LD, Krogstad DJ. 1998. Structure-activity relationships for antiplasmodial activity among 7-substituted 4-aminoquinolines. J. Med. Chem. 41:4918-26
46. van Schalkwyk DA, Walden JC, Smith PJ. 2001. Reversal of chloroquine resistance in Plasmodium falciparum using combinations of chemosensitizers. Antimicrob. Agents Chemother. 45:3171-74
47. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, et al. 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363:9-17
48. Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, et al. 2003. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J. Infect. Dis. 187:1870-75
49. Domagk G. 1935. Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Dtsch. Med. Wochenschr. 61:250-53
50. Hill RA, Goodwin MH Jr. 1937. "Prontosil" in treatment of malaria. South. Med. J. 30:1170-72
51. Curd FHS, Davey DG, Rose FL. 1945. Studies on synthetic antimalarial drugs. X. Some biguanide derivatives as new types of antimalarial substances with both therapeutic and causal prophylactic activity. Ann. Trop. Med. Hyg. 39:208-16
52. Greenberg J, Boyd BL, Josephson ES. 1948. Synergistic effect of chlorguanide and sulfadiazine against Plasmodium gallinaceum in the chick. J. Pharmacol. Exp. Ther. 94:60-64
53. Greenberg J. 1949. The potentiation of the antimalarial activity of chlorguanide by p-aminobenzoic acid competitors. J. Pharmacol. Exp. Ther. 97:238-42
54. Falco EA, Hitchings GH, Russell PB, VanderWerff H. 1949. Antimalarials as antagonists of purines and pteroylglutamic acid. Nature 164:107-8
55. Poe M. 1976. Antibacterial synergism: a proposal for chemotherapeutic potentiation between trimethoprim and sulfamethoxazole. Science 194:533-35
56. Sirawaraporn W, Yuthavong Y. 1986. Potentiating effect of pyrimethamine and sulfadoxine against dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi. Antimicrob. Agents Chemother. 29:899-905
57. Wang P, Brobey RK, Horii T, Sims PF, Hyde JE. 1999. Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy. Mol. Microbiol. 32:1254-62
58. Wang P, Wang Q, Aspinall TV, Sims PF, Hyde JE. 2004. Transfection studies to explore essential folate metabolism and antifolate drug synergy in the human malaria parasite Plasmodium falciparum. Mol. Microbiol. 51:1425-38
59. Rosenblatt DS, Fenton WA. 2001. Inherited disorders of folate and cobalamin transport and metabolism. In The Metabolic and Molecular Bases of Inherited Disease, ed. CR Scriber, AL Beaudet, WS Sly, D Valle, pp. 3897-929. New York; McGraw-Hill
60. Dieckmann A, Jung A. 1986. Mechanisms of sulfadoxine resistance in Plasmodium falciparum. Mol. Biochem. Parasitol. 19:143-47
61. Roberts F, Roberts CW, Johnson JJ, Kyle DE, Krell T, et al. 1998. Evidence for the shikimate pathway in apicomplexan parasites. Nature 393:801-5
62. Kicska GA, Ting LM, Schramm VL, Kim K. 2003. Effect of dietary p-aminobenzoic acid on murine Plasmodium yoelii infection. J. Infect. Dis. 188:1776-81
63. Milhous WK, Weatherly NF, Bowdre JH, Desjardins RE. 1985. In vitro activities of and mechanisms of resistance to antifol antimalarial drugs. Antimicrob. Agents Chemother. 27:525-30
64. Krungkrai J, Webster HK, Yuthavong Y. 1989. De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum. Mol. Biochem. Parasitol. 32:25-37
65. Wang P, Sims PF, Hyde JE. 1997. A modified in vitro sulfadoxine susceptibility assay for Plasmodium falciparum suitable for investigating Fansidar resistance. Parasitology 115:223-30
66. Ferone R. 1973. The enzymic synthesis of dihydropteroate and dihydrofolate by Plasmodium berghei. J. Protozool. 20:459-64
67. Triglia T, Cowman AF. 1994. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 91:7149-53
68. Bzik DJ, Li WB, Horii T, Inselburg J. 1987. Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene. Proc. Natl. Acad. Sci. USA 84: 8360-64
69. Chen GX, Zolg JW. 1987. Purification of the bifunctional thymidylate synthase-dihydrofolate reductase complex from the human malaria parasite Plasmodium falciparum. Mol. Pharmacol. 32:723-30
70. Zhang K, Rathod PK. 2002. Divergent regulation of dihydrofolate reductase between malaria parasite and human host. Science 296:545-47
71. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. 2000. Folic acid antagonists during pregnancy and the risk of birth defects. N. Engl. J. Med. 343:1608-14
72. Bishop A, Birkett B. 1947. Acquired resistance to paludrine in Plasmodium gallinaceum. Nature 159:884-85
73. Plowe CV. 2001. Folate antagonists and mechanisms of resistance. See Ref. 134, pp. 173-90
74. Yuthavong Y. 2002. Basis for antifolate action and resistance in malaria. Microbes. Infect. 4:175-82
75. Cortese JF, Caraballo A, Contreras CE, Plowe CV. 2002. Origin and dissemination of Plasmodium falciparum drug-resistance mutations in South America. J. Infect. Dis. 186:999-1006
76. Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, et al. 2003. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 361:1174-81
77. Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, et al. 2002. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J. Infect. Dis. 185:380-88
78. Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, et al. 1997. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J. Infect. Dis. 176: 1590-96
79. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA, et al. 2004. Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. BMJ 328:545
80. Peterson DS, Walliker D, Wellems TE. 1988. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc. Natl. Acad. Sci. USA 85:9114-18
81. Wang P, Read M, Sims PF, Hyde JE. 1997. 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. 23:979-86
82. Triglia T, Wang P, Sims PF, Hyde JE, Cowman AF. 1998. Allelic exchange at the endogenous genomic locus in Plasmodium falciparum proves the role of dihydropteroate synthase in sulfadoxine-resistant malaria. EMBO J. 17:3807-15
83. Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV. 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. USA 94:1124-29
84. Triglia T, Menting JG, Wilson C, Cowman AF. 1997. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 94:13944-49
85. Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, et al. 2003. Insights into antifolate resistance from malarial DHFR-TS structures. Nat. Struct. Biol. 10:357-65
86. Kamchonwongpaisan S, Quarrell R, Charoensetakul N, Ponsinet R, Vilaivan T, et al. 2004. Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities. J. Med. Chem. 47:673-80
87. Rastelli G, Pacchioni S, Sirawaraporn W, Sirawaraporn R, Parenti MD, et al. 2003. Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors. J. Med. Chem. 46:2834-15
88. Jiang L, Lee PC, White J, Rathod PK. 2000. Potent and selective activity of a combination of thymidine and 1843U89, a folate-based thymidylate synthase inhibitor, against Plasmodium falciparum. Antimicrob. Agents Chemother. 44:1047-50
89. Amukoye E, Winstanley PA, Watkins WM, Snow RW, Hatcher J, et al. 1997. Chlorproguanil-dapsone: effective treatment for uncomplicated falciparum malaria. Antimicrob. Agents Chemother. 41:2261-64
90. Sulo J, Chimpeni P, Hatcher J, Kublin JG, Plowe CV, et al. 2002. Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial. Lancet 360:1136-43
91. Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, et al. 2002. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet 360:2031-38
92. Fieser LF, Berlinger E, Bondhus FJ, Chang FC, Dauben WG, et al. 1948. Naphthoquinone antimalarials I. General survey. J. Am. Chem. Soc. 70:3151-55
93. Hudson AT, Dickins M, Ginger CD, Gutteridge WE, Holdich T, et al. 1991. 566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs Exp. Clin. Res. 17:427-35
94. Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, et al. 1996. 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. 54:62-66
95. Fry M, Pudney M. 1992. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy- 1,4-naphthoquinone (566C80). Biochem. Pharmacol. 43: 1545-53
96. Srivastava IK, Rottenberg H, Vaidya AB. 1997. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J. Biol. Chem. 272:3961-66
97. Srivastava IK, Morrisey JM, Darrouzet E, Daldal F, Vaidya AB. 1999. Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Mol. Microbiol. 33:704-11
98. Korsinczky M, Chen N, Kotecka B, Saul A, Rieckmann K, et al. 2000. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob. Agents Chemother. 44:2100-8
99. Canfield CJ, Pudney M, Gutteridge WE. 1995. Interactions of atovaquone with other antimalarial drugs against Plasmodium falciparum in vitro. Exp. Parasitol. 80:373-81
100. Srivastava IK, Vaidya AB. 1999. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob. Agents Chemother. 43:1334-39
101. Arguin P, Barber A, Kozarsky P, Mali S, Newman R, et al. 2004. Malaria. http://www.edc.gov/travel/diseases/malaria/index.htm
102. Drugs for parasitic infections. 2004. Med. Lett. Drugs Ther. August:1-12
103. Fivelman QL, Butcher GA, Adagu IS, Warhurst DC, Pasvol G. 2002. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malar. J. 1:1
104. Schwartz E, Bujanover S, Kain KC. 2003. Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin. Infect. Dis. 37:450-51
105. Lage H. 2003. ABC-transporters: implications on drug resistance from microorganisms to human cancers. Int. J. Antimicrob. Agents 22:188-99
106. Syafruddin D, Asih PB, Aggarwal SL, Shankar AH. 2003. Frequency distribution of antimalarial drug-resistant alleles among isolates of Plasmodium falciparum in Purworejo district, Central Java Province, Indonesia. Am. J. Trop. Med. Hyg. 69:614-20
107. Rathod PK, McErlean T, Lee PC. 1997. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 94:9389-93
108. Meshnick SR. 2001. Artemisinins and its derivatives. See Ref. 134, pp. 191-202
109. Borstnik K, Paik IH, Shapiro TA, Posner GH. 2002. Antimalarial chemotherapeutic peroxides: artemisinin, yingzhaosu A and related compounds. Int. J. Parasitol. 32:1661-67
110. Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, et al. 2003. Artemisinins target the SERCA of Plasmodium falciparum. Nature 424:957-61
111. Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Eh JP, et al. 1994. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J. Infect. Dis. 170:971-77
112. Geary TG, Jensen JB. 1983. Effects of antibiotics on Plasmodium falciparum in vitro. Am. J. Trop. Med. Hyg. 32:221-25
113. Clyde DF, Gilman RH, McCarthy VC. 1975. Antimalarial effects of clindamycin in man. Am. J. Trop. Med. Hyg. 24:369-70
114. Mahmoudi N, Ciceron L, Franetich JF, Farhati K, Silvie O, et al. 2003. In vitro activities of 25 quinolones and fluoroquinolones against liver and blood stage Plasmodium spp. Antimicrob. Agents Chemother. 47:2636-39
115. McClean KL, Hitchman D, Shafran SD. 1992. Norfloxacin is inferior to chloroquine for falciparum malaria in northwestern Zambia: a comparative clinical trial. J. Infect. Dis. 165:904-7
116. Pfaller MA, Krogstad DJ. 1981. Imidazole and polyene activity against chloroquine-resistant Plasmodium falciparum. J. Infect. Dis. 144:372-75
117. Chong CR, Sullivan DJ Jr. 2003. Inhibition of heme crystal growth by antimalarials and other compounds: implications for drug discovery. Biochem. Pharmacol. 66:2201-12
118. Huy NT, Kamei K, Yamamoto T, Kondo Y, Kanaori K, et al. 2002. Clotrimazole binds to heme and enhances heme-dependent hemolysis: proposed antimalarial mechanism of clotrimazole. J. Biol. Chem. 277:4152-58
119. Olliaro PL, Taylor WR. 2003. Antimalarial compounds: from bench to bedside. J. Exp. Biol. 206:3753-59
120. Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, et al. 2001. A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am. J. Trop. Med. Hyg. 64:247-56
121. Denis MB, Davis TM, Hewitt S, Incardona S, Nimol K, et al. 2002. Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria. Clin. Infect. Dis. 35:1469-76
122. Schellenberg D, Kahigwa E, Drakeley C, Malende A, Wigayi J, et al. 2002. The safety and efficacy of sulfadoxine-pyrimethamine, amodiaquine, and their combination in the treatment of uncomplicated Plasmodium falciparum malaria. Am. J. Trop. Med. Hyg. 67:17-23
123. Guerin PJ, Olliaro P, Nosten F, Druilhe P, Laxminarayan R, et al. 2002. Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development. Lancet Infect. Dis. 2:564-73
124. Surolia N, Surolia A. 2001. Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum. Nat. Med. 7:167-73
125. Joet T, Eckstein-Ludwig U, Morin C, Krishna S. 2003. Validation of the hexose transporter of Plasmodium falciparum as a novel drug target. Proc. Natl. Acad. Sci. USA 100:7476-79
126. Moon RP, Tyas L, Certa U, Rupp K, Bur D, et al. 1997. Expression and characterisation of plasmepsin I from Plasmodium falciparum. Eur. J. Biochem. 244:552-60
127. Francis SE, Gluzman IY, Oksman A, Banerjee D, Goldberg DE. 1996. Characterization of native falcipain, an enzyme involved in Plasmodium falciparum hemoglobin degradation. Mol. Biochem. Parasitol. 83:189-200
128. Greenbaum DC, Baruch A, Grainger M, Bozdech Z, Medzihradszky KF, et al. 2002. A role for the protease falcipain 1 in host cell invasion by the human malaria parasite. Science 298:2002-6
129. Shenai BR, Lee BJ, Alvarez-Hernandez A, Chong PY, Emal CD, et al. 2003. Structure-activity relationships for inhibition of cysteine protease activity and development of Plasmodium falciparum by peptidyl vinyl sulfones. Antimicrob. Agents Chemother. 47:154-60
130. Becker K, Tilley L, Vennerstrom JL, Roberts D, Rogerson S, et al. 2004. Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. Int. J. Parasitol. 34:163-89
131. Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, et al. 1999. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285:1573-76
132. Lell B, Ruangweerayut R, Wiesner J, Missinou MA, Schindler A, et al. 2003. Fosmidomycin, a novel chemotherapeutic agent for malaria. Antimicrob. Agents Chemother. 47:735-38
133. Mandell GL, Douglas RG, Bennett JE, Dolin R, eds. 2000. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone
134. Rosenthal PJ, ed. 2001. Antimalarial Chemotherapy. Totowa, NJ: Humana Press