Chapter 148 : Mechanisms of Resistance to Antiparasitic Agents

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Mechanisms of Resistance to Antiparasitic Agents , Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816728/9781555814632_Chap148-1.gif /docserver/preview/fulltext/10.1128/9781555816728/9781555814632_Chap148-2.gif


The chapter talks about the mechanisms of resistance to antiparasitic agents. , the most virulent species, which adapts more easily to environmental constraints in tropical areas, has become the dominant species, and its resistance to chloroquine, to sulfadoxine-pyrimethamine, and, further, to all known drugs has developed to various degrees. True resistance is more likely in anthroponotic forms of leishmaniasis, such as those caused by and , because the zoonotic species that infect primarily animals, with humans as an occasional host, rarely encounter drugs. Laboratory or field isolates with resistance to pentavalent antimonials are also killed effectively by paromomycin and miltefosine. Several factors contribute to the emergence of drug- resistant parasites. Public health interventions to correct these factors have not always been successful and would benefit from a better understanding of the drug resistance mechanisms used by parasites. These mechanisms are very diverse and have been difficult to study, but recent technological advances now provide long-awaited tools that will facilitate the task. The genome sequences for , , , , and have been compiled. When these data are used, for example, in combination with microarray technology, where the DNA of drug-resistant parasite strains is compared to that of drugsusceptible strains, identification of the genes that confer resistance should proceed even more rapidly than in the last few years.

Citation: Secor W, Le Bras J. 2011. Mechanisms of Resistance to Antiparasitic Agents , p 2296-2306. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch148
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Alonso, D.,, J. Muñoz,, J. Gascón,, M. E. Valls,, and M. Corahan. 2006. Short report: failure of standard treatment with praziquantel in two returned travelers with Schistosoma haematobium infection. Am. J. Trop. Med. Hyg. 74: 342 344.
2. Alvar, J.,, P. Aparaicio,, A. Aseffa,, M. Den Boer,, C. Cañavate,, J.-P. Dedet,, L. Gradoni,, R. Ter Horst,, R. López-Velez,, and J. Moreno. 2008. The relationship between leishmaniasis and AIDS: the second 10 years. Clin. Microbiol. Rev. 21: 334 359.
3. Angelucci, F.,, A. Basso,, A. Bellelli,, M. Brunori,, L. Pica Mattoccia,, and C. Valle. 2007. The anti-schistosomal drug praziquantel is an adenosine antagonist. Parasitology 134: 1215 1221.
4. Ariey, F.,, T. Fandeur,, R. Durand,, M. Randrianarivelojosia,, R. Jambou,, E. Legrand,, M. T. Ekala,, C. Bouchier,, S. Cojean,, J. B. Duchemin,, V. Robert,, J. Le Bras,, and O. Mercereau-Puijalon. 2006. Invasion of Africa by a single pfcrt allele of South East Asian type. Malaria J. 5: 34.
5. Ashutosh,, S. Sundar,, and N. Goyal. 2007. Molecular mechanisms of antimony resistance in Leishmania. J. Med. Microbiol. 56: 143 153.
6. Baird, J. K. 2009. Resistance to therapies for infections by Plasmodium vivax. Clin. Microbiol. Rev. 22: 508 534.
7. Basu, J. M.,, A. Mookerjee,, R. Banerjee,, M. Saha,, S. Singh,, K. Naskar,, G. Tripathy,, P. K. Sinha,, K. Pandey,, S. Sundar,, S. Bimal,, P. K. Das,, S. K. Choudhuri,, and S. Roy. 2008. Inhibition of ABC transporters abolishes antimony resistance in Leishmania infection. Antimicrob. Agents Chemother. 52: 1080 1093.
8. Berman, J. 2005. Recent developments in leishmaniasis: epidemiology, diagnosis, and treatment. Curr. Infect. Dis. Rep. 7: 33 38.
9. Bern, C.,, J. Adler-Moore,, J. Berenguer,, M. Boelaert,, M. Den Boer,, R. N. Davidson,, C. Figueras,, L. Gradoni,, D. A. Kafetzis,, K. Ritmeijer,, E. Rosenthal,, C. Royce,, R. Russo,, S. Sundar,, and J. Alvar. 2006. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin. Infect. Dis. 43: 917 924.
10. Bitonti, A. J.,, A. Sjoerdsma,, P. P. McCann,, D. E. Kyle,, A. M. J. Oduola,, R. N. Rossan,, W. K. Milhous,, and D. E. Davidson, Jr. 1988. Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine. Science 242: 1301 1303.
11. Black, C. L.,, M. L. Steinauer,, P. N. M. Mwinzi,, W. E. Secor,, D. M. S. Karanja,, and D. G. Colley. 2009. Impact of intense, longitudinal retreatment with praziquantel on cure rates of schistosomiasis mansoni in a cohort of occupationally exposed adults in western Kenya. Trop. Med. Int. Health 14: 450 457.
12. Blaha, C.,, M. Duchêne,, H. Aspöck,, and J. Walochnik. 2006. In vitro activity of hexadecylphospocholine (miltefosine) against metronidazole-resistant and -susceptible strains of Trichomonas vaginalis. J. Antimicrob. Chemother. 57: 273 278.
13. Botros, S.,, H. Sayed,, N. Amer,, M. El-Ghannam,, J. L. Bennet,, and T. A. Day. 2005. Current status of sensitivity to praziquantel in a focus of potential drug resistance in Egypt. Int. J. Parasitol. 35: 787 791.
14. Bray, P. G.,, R. E. Martin,, L. Tilley,, S. A. Ward,, K. Kirk,, and D. A. Fidock. 2005. Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. Mol. Microbiol. 56: 323 333.
15. Bray, P. G.,, M. Mungthin,, R. G. Ridley,, and S. A. Ward. 1998. Access to hematin: the basis of chloroquine resistance. Mol. Pharmacol. 54: 170 179.
16. Brega, S.,, B. Meslin,, F. de Montbrison,, C. Severini,, L. Gradoni,, R. Udomsangpetch,, I. Sutanto,, F. Peyron,, and S. Picot. 2005. Identification of the Plasmodium vivax mdr-like gene (pvmdr1) and analysis of single-nucleotide polymorphisms among isolates from different areas of endemicity. J. Infect. Dis. 191: 272 277.
17. Bridges, D. J.,, M. K. Gould,, B. Nerima,, P. Mäser,, R. J. S. Burchmore,, and H. P. de Koning. 2007. Loss of the highaffinity pentamidine transporter is responsible for high levels of cross-resistance between arsenical and diamidine drugs in African trypanosomes. Mol. Pharm. 71: 1098 1108.
17a. Butler, S. E.,, P. Augostini,, and W. E. Secor. 2010. Mycoplasma hominis infection of Trichomonas vaginalis is not associated with metronidazole-resistant trichomoniasis in clinical isolates from the United States. Parasitol. Res. 107: 1023 1027.
18. Carter, K. C.,, S. Sundar,, C. Spickett,, O. C. Pereira,, and A. B. Mullen. 2003. The in vivo susceptibility of Leishmania donovani to sodium stibogluconate is drug specific and can be reversed by inhibiting glutathione biosynthesis. Antimicrob. Agents Chemother. 47: 1529 1535.
19. Castanys-Muñoz, E.,, J. M. Pérez-Victoria,, F. Gamarro,, and S. Castanys. 2008. Characterization of an ABCG-like transporter from the protozoan parasite Leishmania with a role in drug resistance and transbilayer lipid movement. Antimicrob. Agents Chemother. 52: 3573 3579.
20. Cowman, A. F.,, D. Galatis,, and J. K. Thomson. 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.
21. Cowman, A. F.,, M. J. Morry,, B. A. Biggs,, G. A. Cross,, and S. J. Foote. 1988. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 85: 9109 9113.
22. Croft, S. L.,, and G. H. Coombs. 2003. Leishmaniasis— current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol. 19: 502 508.
23. Croft, S. L.,, S. Sundar,, and A. H. Fairlamb. 2006. Drug resistance in leishmaniasis. Clin. Microbiol. Rev. 19: 111 126.
24. Crowell, A. L.,, K. A. Sanders-Lewis,, and W. E. Secor. 2003. In vitro comparison of metronidazole and tinidazole activity against metronidazole resistant strains of Trichomonas vaginalis. Antimicrob. Agents Chemother. 47: 1407 1409.
25. Cudmore, S. L.,, K. L. Delgaty,, S. F. Hayward-McClelland,, D. P. Petrin,, and G. E. Garber. 2004. Treatment of infections caused by metronidazole-resistant Trichomonas vaginalis. 17: 783 793.
26. Curtis, J.,, M. T. Duraisingh,, and D. C. Warhurst. 1998. In vivo selection for a specific genotype of dihydropteroate synthetase of Plasmodium falciparum by sulfadoxine-pyrimethamine but not chlorproguanil-dapsone treatment. J. Infect. Dis. 177: 1429 1433.
27. Dahlstrom, S.,, P. E. Ferreira,, M. I. Veiga,, N. Sedighi,, L. Waklund,, A. Martensson,, A. Farnert,, C. Sissowath,, L. Ossorio,, H. Darban,, B. Andersson,, A. Kaneko,, G. Conseil,, A. Bjorkman,, and J. P. Gil. 2009. Plasmodium falciparum multidrug resistance protein 1 ( PfMRP1) and artemisinin-based combination therapy in Africa. J. Infect. Dis. 200: 1456 1464.
28. de Koning, H. P. 2008. Ever-increasing complexities of diamidine and arsenical crossresistance in African trypanosomes. Trends Parasitol. 24: 345 349.
29. Delespaux, V.,, and H. P. de Koning. 2007. Drugs and drug resistance in African trypanosomiasis. Drug Resist. Updat. 10: 30 50.
30. de Pécoulas, P. E.,, L. K. Basco,, J. Le Bras,, and A. Mazabraud. 1996. Association between antifolate resistance in vitro and DHFR gene point mutation in Plasmodium falciparum isolates. Trans. R. Soc. Trop. Med. Hyg. 90: 181 182.
31. Djimdé, A. A.,, A. Dolo,, A. Ouattara,, S. Diakité,, C. V. Plowe,, and O. K. Doumbo. 2004. Molecular diagnosis of resistance to antimalarial drugs during epidemics and in war zones. J. Infect. Dis. 190: 853 855.
32. Djimdé, A.,, O. K. Doumbo,, J. F. Cortese,, K. Kayentao,, S. Doumbo,, Y. Diourté,, A. Dicko,, X. Su,, T. Nomura,, D. A. Fidock,, T. E. Wellems,, and C. V. Plowe. 2001. A molecular marker for chloroquine-resistant falciparum malaria. N. Engl. J. Med. 344: 257 263.
33. Djimdé, A.,, O. K. Doumbo,, R. W. Steketee,, and C. V. Plowe. 2001. Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria. Lancet 358: 890 891.
34. Doenhoff, M. J.,, D. Cioli,, and J. Utzinger. 2008. Praziquantel: mechanism of action, resistance and new derivatives for schistosomiasis. Curr. Opin. Infect. Dis. 21: 659 667.
35. Doenhoff, M. J.,, P. Hagan,, D. Cioli,, V. Southgate,, L. Pica- Mattoccia,, S. Botros,, G. Coles,, L. A. Tchuem Tchuente,, A. Mbaye,, and D. Engels. 13 March 2009. Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs. Parasitology. doi:10.1017/S0031182009000493.
36. Dorsey, G.,, D. A. Fidock,, T. E. Wellems,, and P. J. Rosenthal,. 2001. Mechanisms of quinoline resistance, p. 153 172. In P. J. Rosenthal (ed), Antimalarial Chemotherapy. Mechanisms of Action, Resistance, and New Directions in Drug Discovery. Humana Press, Totowa, NJ.
37. Dube, A.,, N. Singh,, S. Sundar,, and N. Singh. 2005. Refractoriness to treatment of sodium stibogluconate in Indian kala-azar field isolates persist in in vitro and in vivo experimental models. Parasitol. Res. 96: 216 223.
38. Dunne, R. L.,, L. A. Dunn,, P. Upcroft,, P. J. O’Donoghue,, and J. A. Upcroft. 2003. Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis. Cell Res. 13: 239 249.
39. Duraisingh, M. T.,, C. Roper,, D. Walliker,, and D. C. Warhurst. 2000. Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum. Mol. Microbiol. 36: 955 961.
40. El Fadili, K.,, N. Messier,, P. Leprohon,, G. Roy,, C. Guimond,, N. Trudel,, N. G. Saravia,, B. Papadopoulou,, D. Légaré,, and M. Ouellette. 2005. Role of the ABC transporter MRPA (PGPA) in antimony resistance in Leishmania infantum axenic and intracellular amastigotes. Antimicrob. Agents Chemother. 49: 1988 1993.
41. Fallon, T. G.,, R. F. Sturrock,, C. M. Niang,, and M. J. Doenhoff. 1995. Diminished susceptibility to praziquantel in a Senegal isolate of Schistosoma mansoni. Am. J. Trop. Med. Hyg. 53: 61 62.
42. Fidock, D. A.,, T. Nomura,, A. K. Talley,, R. A. Cooper,, S. M. Dzekunov,, M. T. Ferdig,, L. M. B. Ursos,, A. B. S. Sidhu,, B. Naudé,, K. W. Deitsch,, X. Su,, J. C. Wootton,, P. D. Roepe,, and T. E. Wellems. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6: 861 871.
43. Fitch, C. D. 1970. Plasmodium falciparum in owl monkeys: drug resistance and chloroquine binding capacity. Science 169: 289 290.
44. Foote, S. J.,, D. Galatis,, and A. F. Cowman. 1990. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc. Nat. Acad. Sci. USA 87: 3014 3017.
45. Gnanasekar, M.,, A. M. Salunkhe,, A. K. Mallia,, Y. X. He,, and R. Kalyanasundaram. 2009. Praziquantel affects the regulatory myosin light chain of Schistosoma mansoni. Antimicrob. Agents Chemother. 53: 1054 1060.
46. Gourbal, B.,, N. Sounu,, H. Bhattacharjee,, D. Legare,, S. Sundar,, M. Ouellette,, B. P. Rosen,, and R. Mukhopadhyay. 2004. Drug uptake and modulation of resistance in Leishmania by an aquaglyceroporin. J. Biol. Chem. 279: 31010 31017.
47. Hampl, V.,, S. Vannáacová,, J. Kulda,, and J. Fleger. 2001. Concordance between genetic relatedness and phenotypic similarities of Trichomonas vaginalis strains. BMC Evol. Biol. 1: 11.
48. Happi, C. T.,, G. O. Gbotosho,, O. A. Folarin,, A. Sowunmi,, T. Hudson,, M. O’Neil,, W. Milhous,, D. F. Wirth,, and A. M. J. Oduola, 2009. Selection of P. falciparum multidrug resistance gene 1 alleles in asexual stages and gametocytes by artemetherlumefantrine in Nigerian children with uncomplicated falciparum malaria. Antimicrob. Agents Chemother. 53: 888 895.
49. Harms, G.,, and H. Feldmeier. 2005. The impact of HIV infection on tropical diseases. Infect. Dis. Clin. N. Am. 19: 121 135.
50. Hastings, M. D.,, K. M. Porter,, J. D. Maguire,, I. Susanti,, W. Kania,, M. J. Bangs,, C. H. Sibley,, and J. K. Baird. 2003. Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine. J. Infect. Dis. 189: 744 750.
51. Helms, D. J.,, D. J. Mosure,, W. E. Secor,, and K. A. Workowski. 2008. Management of Trichomonas vaginalis in women with suspected metronidazole hypersensitivity. Am. J. Obstet. Gynecol. 198: 370.e1 370.e7.
52. Hrdý, I.,, R. Cammack,, P. Stopka,, J. Kulda,, and J. Tachezy. 2005. Alternative pathway of metronidazole activation in Trichomonas vaginalis hydrogenosomes. Antimicrob. Agents. Chemother. 49: 5033 5036.
53. Ismail, M.,, S. Botros,, A. Metwally,, S. William,, A. Farghally,, L. F. Tao,, T. A. Day,, and J. L. Bennett. 1999. Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers. Am. J. Trop. Med. Hyg. 60: 932 935.
54. Ismail, M.,, A. Metwally,, A. Farghaly,, J. Bruce,, L.-F. Tao,, and J. L. Bennett. 1996. Characterization of isolates of Schistosoma mansoni from Egyptian villagers that tolerate high doses of praziquantel. Am. J. Trop. Med. Hyg. 55: 214 218.
55. Jeziorski, M. C.,, and R. M. Greenberg. 2006. Voltage-gated calcium channel subunits from platyhelminths: potential role in praziquantel action. Int. J. Parasitol. 36: 625 632.
56. Jhingran, A.,, B. Chawla,, S. Saxena,, M. P. Barrett,, and R. Madhubala. 2009. Paromomycin: uptake and resistance in Leishmania donovani. Mol. Biochem. Parasitol. 164: 111 117.
57. Karanja, D. M. S.,, A. E. Boyer,, M. Strand,, D. G. Colley,, B. L. Nahlen,, J. H. Ouma,, and W. E. Secor. 1998. Studies on schistosomiasis in western Kenya. II. Efficacy of praziquantel for schistosomiasis patients with human immunodeficiency virus co-infections. Am. J. Trop. Med. Hyg. 59: 307 311.
58. Kibona, S. N.,, L. Metamba,, J. S. Kabonya,, and G. W. Lubega. 2006. Drug-resistance of Tryapanosoma b. rhodesiense isolates from Tanzania. Trop. Med. Int. Health 11: 144 155.
59. King, C. H.,, E. M. Muchiri,, and J. H. Ouma. 2000. Evidence against rapid emergence of praziquantel resistance in Schistosoma haematobium, Kenya. Emerg. Infect. Dis. 6: 585 594.
60. Korsinczky, M.,, N. Chen,, B. Kotecka,, A. Saul,, K. Rieckmann, and Q. Cheng. 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 2108.
61. Korsinczky, M.,, K. Fisher,, N. Chen,, J. Baker,, and Q. Cheng. 2004. Sulfadoxine resistance in Plasmodium vivax is associated with a specific amino acid in dihydropteroate synthase at the putative sulfadoxine-binding site. Antimicrob. Agents Chemother. 48: 2214 2222.
62. Krogstad, D. J.,, I. Y. Gluzman,, D. E. Kyle,, A. M. J. Oduola,, S. K. Martin,, W. K. Milhous,, and P. H. Schlesinger. 1987. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238: 1283 1285.
63. Kublin, J. G.,, F. K. Dzinjalamala,, D. D. Kamwendo,, E. M. Malkin,, J. F. Cortese,, L. M. Martino,, R. A. G. Mukadam,, S. J. Rogerson,, A. G. Lescano,, M. E. Molyneux,, P. A. Winstanley,, P. Chimpeni,, T. E. Taylor,, and C. V. Plowe. 2002. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J. Infect. Dis. 185: 380 388.
64. Kumar, D.,, A. Kulshrestha,, R. Singh,, and P. Solotra. 2009. In vitro susceptibility of field isolates of Leishmania donovani to miltefosine and amphotericin B: correlation with sodium antimony gluconate susceptibility and implications for treatment in areas of endemicity. Antimicrob. Agents Chemother. 53: 835 838.
65. Lachaud, L.,, N. Bourgeois,, M. Plourde,, P. Leprohon,, P. Bastien,, and M. Ouellette. 2009. Parasite susceptibility to amphotericin B in failures of treatment for visceral leishmaniasis in patients coinfected with HIV type 1 and Leishmania infantum. Clin. Infect. Dis. 48: e16 e22.
66. Land, K. M.,, M. G. Delgadillo,, and P. J. Johnson. 2002. In vivo expression of ferredoxin in a drug resistant trichomonad increases metronidazole susceptibility. Mol. Biochem. Parasitol. 121: 153 157.
67. Légaré, D.,, D. Richard,, R. Mukhopadhyay,, Y.-D. Stierhof,, B. P. Rosen,, A. Haimeur,, B. Papadopoulou,, and M. Ouellette. 2001. The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J. Biol. Chem. 278: 26301 26307.
68. Leitsch, D.,, D. Kolarich,, M. Binder,, J. Stadlmann,, F. Altmann,, and M. Duchêne. 2009. Trichomonas vaginalis: metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system. Implications for nitroimidazole toxicity and resistance. Mol. Microbiol. 72: 518 536.
69. Li, Y.-S.,, H.-G. Chen,, H.-B. He,, X.-Y. Hou,, M. Ellis,, and D. P. McManus. 2005. A double-blind field trial on the effects of artemether on Schistosoma japonicum infection in a highly endemic focus in southern China. Acta Trop. 96: 184 190.
70. Liang, Y.-S.,, G. C. Coles,, J.-R. Dai,, Y.-C. Zhu,, and M. J. Doenhoff. 2002. Adult worm tegumental damage and egggranulomas in praziquantel-resistant and -susceptible Schistosoma mansoni treated in vivo. J. Helminthol. 76: 327 333.
71. Liang, Y. S.,, G. C. Coles,, M. J. Doenhoff,, and V. R. Southgate. 2001. In vitro responses of praziquantel-resistant and -susceptible Schistosoma mansoni to praziquantel. Int. J. Parasitol. 31: 1227 1235.
72. Lim, P.,, A. P. Alker,, N. Khim,, N. K. Shah,, S. Incardona,, S. Doung,, P. Yi,, M. B. Denis,, C. Bouchier,, O. Puijalon,, S. R. Meshnick,, C. Wongsrichanalai,, T. Fandeur,, J. Le Bras,, P. Ringwald,, and F. Ariey. 2009. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malaria J. 8: 11.
73. Looareesuwan, S. C.,, C. Viravan,, H. K. Webster,, D. E. Kyle,, D. B. Hutchinson,, and C. J. Canfield. 1996. Clinical studies on atovaquone, alone or in association with other antimalarial drugs for treatment of acute uncomplicated malaria in Thailand. Am. J. Trop. Med. Hyg. 54: 62 66.
74. Lozovsky, E. R.,, T. Chookajorn,, K. M. Brown,, M. Imwong,, P. J. Shaw,, S. Kamchonwongpaisan,, D. E. Neafsey,, D. M. Weinreich,, and D. L. Hartl. 2009. Stepwise acquisition of pyrimethamine resistance in the malaria parasite. Proc. Natl. Acad. Sci. USA 106: 12025 12030.
75. Lüscher, A.,, B. Nerima,, and P. Mäser. 2006. Combined contributions of TbAT1 and TbMRPA to drug resistance in Trypanosoma brucei. Mol. Biochem. Parasitol. 150: 364 366.
76. Mahendra, M.,, S. Singh,, M. Chatterjee,, and R. Madhubala. 2008. Role of aquaglyceroporin (AQP1) gene and drug uptake in antimony-resistant clinical isolates of Leishmania donovani. Am. J. Trop. Med. Hyg. 79: 69 75.
77. Maiga, O.,, A. Djimde,, V. Hubert,, A. Aubouy,, F. Kironde,, B. Nsimba,, K. Koram,, O. Doumbo,, J. Le Bras,, and J. Clain. 2007. A shared Asian origin of the triple mutant dhfr allele in P. falciparum from sites across Africa. J. Infect. Dis. 196: 165 172.
78. Maina, N.,, K. J. Maina,, P. Mäser,, and R. Brun. 2007. Genotypic and phenotypic characterization of Trypanosoma brucei gambiense isolates from Ibba, South Sudan, an area of high melarsoprol treatment failure rate. Acta Trop. 104: 84 90.
79. Mandal, G.,, S. Wyllie,, N. Singh,, S. Sundar,, A. H. Fairlamb,, and M. Chatterjee. 2007. Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony. Parasitology 134: 1679 1687.
80. Martin, S. K.,, A. M. J. Oduola,, and W. K. Milhous. 1987. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235: 899 901.
81. McClelland, R. S. 2008. Trichomonas vaginalis infection: can we afford to do nothing? J. Infect. Dis. 197: 487 489.
82. Mead, J. R.,, M. Fernadez,, P. A. Romagnoli,, and W. E. Secor. 2006. Use of Trichomonas vaginalis clinical isolates to evaluate correlation of gene expression and metronidazole resistance. J. Parasitol. 92: 196 199.
83. Mehlotra, R. K.,, H. Fujioka,, P. D. Roepe,, O. Janneh,, L. M. B. Ursos,, V. Jacobs-Lorena,, D. T. McNamara,, M. J. Bockarie,, J. W. Kazura,, D. E. Kyle,, and D. A. Fidock. 2001. Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America. Proc. Natl. Acad. Sci. USA 98: 12689 12694.
84. Melman, S. D.,, M. L. Steinauer,, C. Cunnungham,, L. S. Kubatko,, I. N. Mwangi,, N. B. Wynn,, M. W. Mutuku,, D. M. S. Karanja,, D. G. Colley,, C. Black,, W. E. Secor,, G. M. Mkoji,, and E. S. Loker. 2009. Reduced susceptibility to praziquantel among naturally occurring Kenyan isolates of Schistosoma mansoni. PLoS Negl. Trop. Dis. 3: e504. doi:10.1371/ journal.pntd.0000504.
85. Messerli, S. M.,, R. S. Kasinathan,, W. Morgan,, S. Spranger,, and R. M. Greenberg. 2009. Schistosoma mansoni P-glycoprotein levels increase in response to praziquantel exposure and correlate with reduced praziquantel susceptibility. Mol. Biochem. Parasitol. 167: 54 59.
86. Mishra, J.,, A. Saxena,, and S. Singh. 2007. Chemotherapy of leishmaniasis: past, present, and future. Curr. Med. Chem. 14: 1153 1169.
87. Mita, T.,, A. Kaneko,, J. K. Lum,, B. Bwijo,, M. Takechi,, I. L. Zungu,, T. Tsukahara,, K. Tanabe,, T. Kobayakawa,, and A. Björkmann. 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.
88. Mittal, M. K.,, S. Rai,, Ashutosh,, Ravinder,, S. Gupta,, S. Sundar,, and N. Goyal. 2007. Characterization of natural antimony resistance in Leishmania donovani isolates. Am. J. Trop. Med. Hyg. 76: 681 688.
89. Mueller, M.,, K. Ritmeijer,, M. Balasegaram,, Y. Koummuki,, M. R. Santana,, and R. Davidson. 2007. Unresponsiveness to AmBiosome in some Sudanese patients with kala-azar. Trans. R. Soc. Trop. Med. Hyg. 101: 19 24.
90. Mukherjee, A.,, P. K. Padmanabhan,, S. Singh,, G. Roy,, I. Girard,, M. Chatterjee,, M. Ouellette,, and R. Madhubala. 2007. Role of ABC transporter MRPA, γ -glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. J. Antimicrob. Chemother. 59: 204 211.
91. Murray, H. W. 2004. Treatment of visceral leishmaniasis in 2004. Am. J. Trop. Med. Hyg. 71: 787 794.
92. Musset, L.,, J. Le Bras,, and J. Clain. 2007. Parallel evolution of adaptive mutations in Plasmodium falciparum mitochondrial DNA during atovaquone-proguanil treatment. Mol. Biol. Evol. 24: 1582 1585.
93. Nanda, N.,, R. G. Michel,, G. Kurdgelashvili,, and K. A. Wendel. 2006. Trichomoniasis and its treatment. Expert Rev. Anti Infect. Ther. 4: 125 135.
94. Natera, S.,, C. Machuca,, M. Padrón-Nieves,, A. Moerao,, E. Díaz,, and A. Ponte-Sucre. 2007. Leishmania spp.: proficiency of drug-resistant parasites. Int. J. Antimicrob. Agents 29: 637 642.
95. Nerima, B.,, E. Matovu,, G. W. Lubega,, and J. C. K. Enyaru. 2007. Detection of mutant P2 adenosine transporter (TbAT1) gene in Trypanosoma brucei gambiense isolates from northwest Uganda using allele-specific polymerase chain reaction. Trop. Med. Int. Health 12: 1361 1368.
96. N’Goran, E. K.,, J. Utzinger,, H. N. Gnaka,, A. Yapi,, N. A. N’Guessan,, S. D. Kigbafori,, C. Lengeler,, J. Chollet,, X. Shuhua,, and M. Tanner. 2003. Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. Am. J. Trop. Med. Hyg. 68: 24 32.
97. Nogi, T.,, D. Zhang,, J. D. Chan,, and J. S. Marchant. 2009. A novel biological activity of praziquantel requiring voltage-operated Ca 2+ channel β subunits: subversion of flatworm regenerative polarity. PLoS Negl. Trop. Dis. 3: e464. doi:10.1371/journal.pntd.0000464.
98. Nomura, T.,, J. M.-R. Carlton,, J. K. Baird,, H. A. del Portillo,, D. J. Fryauff,, D. Rathore,, D. A. Fidock,, X.-Z. Su,, W. E. Collins,, T. F. McCutchan,, J. C. Wootton,, and T. E. Wellems. 2001. Evidence for different mechanisms of chloroquine resistance in 2 Plasmodium species that cause human malaria. J. Infect. Dis. 183: 1653 1661.
99. Nyirjesy, P.,, J. D. Sobel,, M. V. Weitz,, D. J. Leaman,, and S. P. Gelone. 1998. Difficult-to-treat trichomoniasis: results with paromomycin cream. Clin. Infect. Dis. 26: 986 988.
100. Nzila, A.,, E. Ochong,, E. Nduati,, K. Gilbert,, P. Winstanley,, S. Ward,, and K. Marsh. 2005. Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet? Trans. R. Soc. Trop. Med. Hyg. 99: 341 346.
101. Olliaro, P. L.,, P. J. Guerrin,, S. Gerstl,, A. A. Haakjolk,, J.-A. Rottingen,, and S. Sundar. 2005. Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980-2004. Lancet Infect. Dis. 5: 763 774.
102. Ouellette, M. 2001. Biochemical and molecular mechanisms of drug resistance in parasites. Trop. Med. Int. Health 6: 874 882.
103. Peters, W., 1970. Drug resistance in human malarias. I. Drugs influencing folic acid metabolism, p. 364 425. In W. Peters (ed), Chemotherapy and Drug Resistance in Malaria. Academic Press, London, United Kingdom.
104. Pica-Mattoccia, L.,, M. J. Doenhoff,, C. Valle,, A. Basso,, A.-R. Troiani,, P. Liberti,, A. Festucci,, A. Guidi,, and D. Cioli. 2009. Genetic analysis of decreased praziquantel sensitivity in a laboratory strain of Schistosoma mansoni. Acta Trop. 111: 82 85.
105. Pica-Mattoccia, L.,, T. Orsini,, A. Basso,, A. Festucci,, P. Liberti,, A. Guidi,, A.-L. Marcatto-Maggi,, S. Nobre-Santana,, A.-R. Troiani,, D. Cioli,, and C. Valle. 2008. Schistosoma mansoni: lack of correlation between praziquantel-induced intra-worm calcium influx and parasite death. Exp. Parasitol. 119: 332 335.
106. Picquet, M.,, J. Vercruysse,, D. J. Shaw,, M. Diop,, and A. Ly. 1998. Efficacy of praziquantel against Schistosoma mansoni in northern Senegal. Trans. R. Soc. Trop. Med. Hyg. 92: 90 93.
107. Plowe, C. V., 2001. Folate antagonists and mechanisms of resistance, p. 173 190. In P. J. Rosenthal (ed.), Antimalarial Chemotherapy. Mechanisms of Action, Resistance, and New Directions in Drug Discovery. Humana Press, Totowa, NJ.
108. Plowe, C. V.,, J. F. Cortese,, A. Djimde,, O. C. Nwanyanwu,, W. M. Watkins,, P. A. Winstanley,, J. G. Estrada-Franco,, R. E. Mollinedo,, J. C. Avila,, J. L. Cespedes,, D. Carter,, and O. Doumbo. 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.
109. Price, R. N.,, A.-C. Uhlemann,, A. Brockman,, R. McGready,, E. Ashley,, L. Phaipun,, R. Patel,, K. Laing,, S. Looareesuwan,, N. J. White,, F. Nosten,, and S. Krishna. 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364: 438 447.
110. Reed, M. B.,, K. J. Saliba,, S. R. Caruana,, K. Kirk,, and A. F. Cowman. 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403: 906 909.
111. Rieckmann, K. H.,, D. R. Davis,, and D. C. Hutton. 1989. Plasmodium vivax resistance to chloroquine? Lancet ii: 1183 1184.
112. Rijal, S.,, V. Yardley,, F. Chappuis,, S. Decuypere,, B. Khanal,, R. Singh,, M. Boelaert,, S. De Doncker,, S. Croft,, and J.-C. Dujardin. 2007. Antimonial treatment of visceral leishmaniasis: are current in vitro susceptibility assays adequate for prognosis of in vivo therapy outcome? Microbes Infect. 9: 529 535.
113. Sánchez-Cañete, M. P.,, L. Carvalho,, F. J. Pérez-Victoria,, F. Gamarro,, and S. Castanys. 2009. Low plasma membrane expression of the miltefosine transport complex renders Leishmania braziliensis refractory to the drug. Antimicrob. Agents Chemother. 53: 1305 1313.
114. Sayed, A. A.,, A. Simeonov,, C. J. Thomas,, J. Inglese,, C. P. Austin,, and D. L. Williams. 2008. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nat. Med. 14: 407 412.
115. Schraner, C.,, B. Hasse,, U. Hasse,, D. Baumann,, A. Faeh,, G. Burg,, F. Grimm,, A. Mathis,, R. Weber,, and H. F. Günthard. 2005. Successful treatment with miltefosine of disseminated cutaneous leishmaniasis in a severely immunocompromised patient infected with HIV-1. Clin. Infect. Dis. 40: 120 124.
116. Schwartz, E.,, S. Bujanover,, and K. C. Kain. 2003. Genetic confirmation of atovaquone-proguanil-resistant P. falciparum malaria acquired by a non immune traveller to East Africa. Clin. Infect. Dis. 37: 450 451.
117. Schwebke, J. R.,, and F. J. Barrientes. 2006. Prevalence of Trichomonas vaginalis isolates with resistance to metronidazole and tinidazole. Antimicrob. Agents Chemother. 50: 4209 4210.
118. Seifert, K.,, S. Matu,, F. J. Pérez-Victoria,, S. Castanys,, F. Gamarro,, and S. L. Croft. 2003. Characterisation of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int. J. Antimicrob. Agents 22: 380 387.
119. Seifert, K.,, F. J. Pérez-Victoria,, M. Stettler,, M. P. Sánchez- Cañete,, S. Castanys,, F. Gamarro,, and S. L. Croft. 2007. Inactivation of the miltefosine transporter, LdMT, causes miltefosine resistance that is conferred to the amastigote stage of Leishmania donovani and persists in vivo. Int. J. Antimicrob. Agents 30: 229 235.
120. Shaked-Mishan, P.,, N. Ulrich,, M. Ephros,, and D. Zilberstein. 2001. Novel intracellular SB v reducing activity correlates with antimony susceptibility in Leishmania donovani. J. Biol. Chem. 276: 3971 3976.
121. Singh, N.,, R. Almeida,, H. Kothari,, P. Kumar,, G. Mandal,, M. Chatterjee,, S. Venkatachalam,, M. K. Govind,, S. K. Mandal,, and S. Sundar. 2007. Differential gene expression analysis in antimony-unresponsive Indian kala azar (visceral leishmaniasis) clinical isolates by DNA microarray. Parasitology 134: 777 787.
122. Sirawaraporn, W.,, S. Sathitkul,, R. Sirawaraporn,, Y. Yuthavong,, and D. V. Santi. 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. USA 94: 1124 1129.
123. Smoak, B. L.,, R. F. DeFraites,, A. J. Magill,, K. C. Kain,, and B. T. Wellde. 1997. Plasmodium vivax infections in U.S. Army troops: failure of primaquine to prevent relapse in studies from Somalia. Am. J. Trop. Med. Hyg. 56: 231 234.
124. Snipes, L. J.,, P. M. Gamard,, E. M. Narcisi,, C. B. Beard,, T. Lehmann,, and W. E. Secor. 2000. Molecular epidemiology of metronidazole resistance in a population of Trichomonas vaginalis clinical isolates. J. Clin. Microbiol. 38: 3004 3009.
125. Sobel, J. D.,, V. Nagappan,, and P. Nyirjesy. 1999. Metronidazole- resistant vaginal trichomoniasis—an emerging problem. N. Engl. J. Med. 341: 292 293.
126. Srivastava, I. K.,, and A. B. Vaidya. 1999. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob. Agents Chemother. 43: 1334 1339.
127. Stelma, F. F.,, I. Talla,, S. Sow,, A. Kongs,, M. Niang,, K. Polman,, A. M. Deelder,, and B. Gryseels. 1995. Efficacy and side effects of praziquantel in an epidemic focus of Schistosoma mansoni. Am. J. Trop. Med. Hyg. 53: 167 170.
128. Sundar, S. 2001. Drug resistance in Indian visceral leishmaniasis. Trop. Med. Int. Health 6: 849 854.
129. Sundar, S.,, and P. L. Olliaro. 2007. Miltefosine in the treatment of leishmaniasis: clinical evidence for informed clinical risk management. Ther. Clin. Risk Manag. 3: 733 740.
130. Talisuna, A. O.,, P. Bloland,, and H. D’Alessandro. 2004. History, dynamics and public health importance of malaria parasites resistance. Clin. Microbiol. Rev. 17: 235 254.
131. Triglia, T.,, P. Wang,, P. F. Sims,, J. E. Hyde,, and A. F. Cowman. 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 3815.
132. Upcroft, P.,, and J. A. Upcroft. 2001. Drug targets and mechanisms of resistance in anaerobic protozoa. Clin. Microbiol. Rev. 14: 150 164.
133. Utzinger, J.,, E. K. N’Goran,, A. N’Dri,, C. Lengeler,, and M. Tanner. 2000. Efficacy of praziquantel against Schistosoma mansoni with particular consideration for intensity of infection. Trop. Med. Int. Health 5: 771 778.
134. Utzinger, J.,, E. K. N’Goran,, A. N’Dri,, C. Lengeler,, S. Xiao,, and M. Tanner. 2000. Oral artemether for prevention of Schistosoma mansoni infection: randomized controlled trial. Lancet 355: 1320 1325.
135. Valle, C. A.,, R. Troiani,, A. Festucci,, L. Pica-Mattoccia,, P. Liberti,, A. Wolstenholme,, K. Francklow,, M. J. Doenhoff,, and D. Cioli. 2003. Sequence and level of endogenous expression of calcium channel β subunits in Schistosoma mansoni displaying different susceptibilities to praziquantel. Mol. Biochem. Parasitol. 130: 111 115.
136. Vanacova, S.,, J. Tachezy,, J. Kulda,, and J. Flegr. 1997. Characterization of trichomonad species and strains by PCR fingerprinting. J. Eukaryot. Microbiol. 44: 545 552.
137. van der Pol, B. 2007. Trichomonas vaginalis infection: the most prevalent nonviral sexually transmitted infection receives the least public health attention. Clin. Infect. Dis. 44: 23 25.
138. Verdier, F.,, J. Le Bras,, F. Clavier,, I. Hatin,, and M. C. Blayo. 1985. Chloroquine uptake by P. falciparum infected human red blood cells during in vitro culture. Relationship between chloroquine resistance and uptake. Antimicrob. Agents Chemother. 27: 561 564.
139. Wang, P.,, M. Read,, P. F. G. Sims,, and J. E. Hyde. 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: 979 986.
140. Waters, L. J.,, S. S. Dave,, J. R. Deayton,, and P. D. French. 2005. Recalcitrant Trichomonas vaginalis infection—a case series. Int. J. STD AIDS 16: 505 509.
141. Wellems, T. E.,, L. J. Panton,, I. Y. Gluzman,, V. E. do Rosario,, R. W. Gwadz,, A. Walker-Jonah,, and D. J. Krogstad. 1990. Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345: 253 255.
142. Wellems, T. E.,, and C. V. Plowe. 2001. Chloroquineresistant malaria. J. Infect. Dis. 184: 770 776.
143. Wendel, K. A.,, and K. A. Workowski. 2007. Trichomoniasis: challenges to appropriate management. Clin. Infect. Dis. 44: S123 S129.
144. William, S.,, S. Botros,, M. Ismail,, A. Farghally,, T. A. Day,, and J. L. Bennett. 2001. Praziquantel-induced tegumental damage in vitro is diminished in schistosomes derived from praziquantel-resistant infections. Parasitology 122: 63 66.
145. World Health Organization. 1993. A global strategy for malaria control. World Health Organization, Geneva, Switzerland.
146. Kibona, World Health Organization. 2008. World malaria report. World Health Organization, Geneva, Switzerland.
147. Xiao, J. C.,, L. F. Xie,, S. L. Fang,, M. Y. Gao,, Y. Zhu,, L. Y. Song,, H. M. Zhong,, and Z. R. Lun. 2006. Symbiosis of Mycoplasma hominis in Trichomonas vaginalis may link metronidazole resistance in vitro. Parasitol. Res. 100: 123 130.
148. Xiao, S.-H.,, J. Keiser,, J. Chollet,, J. Utzinger,, Y. Dong,, Y. Endriss,, J. L. Vennerstrom,, and M. Tanner. 2007. In vitro and in vivo activities of synthetic trioxolanes against major human schistosome species. Antimicrob. Agents Chemother. 51: 1440 1445.
149. Yardley, V.,, and S. L. Croft. 1997. Activity of liposomal amphotericin B against experimental cutaneous leishmaniasis. Antimicrob. Agents Chemother. 41: 752 756.
150. Yardley, V.,, N. Ortuño,, A. Llanos-Cuentas,, F. Chappius,, S. De Doncker,, L. Ramirez,, S. Croft,, J. Arevalo,, V. Adaui,, H. Bermudez,, S. Decuypere,, and J.-C. Dujardin. 2006. American tegumentary leishmaniasis: is antimonial treatment outcome related to parasite drug susceptibility? J. Infect. Dis. 194: 1168 1175.


Generic image for table

Summary of proposed mechanisms of resistance to selected antiparasitic drugs

Disease caused predominantly by , , , and .

Disease caused by Trichomonas vaginalis.

Diseases caused by one of several species.

Disease caused by subsp. rhodesiense and subsp. gambiense.

caused predominantly by , , and .

Citation: Secor W, Le Bras J. 2011. Mechanisms of Resistance to Antiparasitic Agents , p 2296-2306. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch148

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error