Parasitology Research

, 109:1225 | Cite as

Leishmania antimony resistance: what we know what we can learn from the field

  • Khatima Aït-Oudhia
  • Elodie Gazanion
  • Baptiste Vergnes
  • Bruno Oury
  • Denis Sereno


Leishmania is the causative agent of various forms of leishmaniasis, a significant cause of morbidity and mortality. The clinical manifestations of the disease range from self-healing cutaneous and mucocutaneous skin ulcers to a fatal visceral form named visceral leishmaniasis or kala-azar. In the absence of any effective vaccine, the only means to treat and control leishmaniasis is affordable medication. The treatment choice is essentially directed by economic considerations; therefore, for a large majority of countries, chemotherapy relies only on the use of cheaper antimonial compounds. The emergence of antimonial therapy failure in India linked to proven parasite resistance has stressed questions about selective factors as well as transmission risk of drug resistance. Unfortunately, in most parts of the world, the frequency of parasite antimony resistance linked to treatment failure is unknown because of a lack of information on Leishmania antimony susceptibility. This information is crucial for addressing the risk of selection and transmission of drug-resistant parasites, particularly in areas where antimony is the only chemotherapeutic alternative. However, the poor knowledge about factors that favor selection of resistant parasites, the multiplicity of the agents that can play a role in the in vivo antileishmanial activity of antimony, and the lack of a standard protocol to diagnose and survey parasite resistance all contribute to insufficient monitoring of antimony resistance. In this review, we discuss on the factors potentially involved in the selection of antimony resistance in the field and discuss on the methods available for its diagnosis.


Antimony Visceral Leishmaniasis Leishmaniasis Parasite Resistance Leishmania Species 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by a grant (AAP2008-Nicomed) from the Département Valorisation Sud (DVS) of IRD. EG is supported by a Higher Education and Research Ministerial grant (France). DS, BO, and BV are supported by Institut de Recherche pour le Développement (IRD).


  1. Aarestrup FM (1999) Association between the consumption of antimicrobial agents in animal husbandry and the occurrence of resistant bacteria among food animals. Int J Antimicrob Agents 12:279–285PubMedCrossRefGoogle Scholar
  2. Abdo MG, Elamin WM, Khalil EAG, Mukhtar MM (2003) Antimony-resistant Leishmania donovani in eastern Sudan: incidence and in vitro correlation. East Mediterr Health J 9:837–843PubMedGoogle Scholar
  3. Adaui V, Schnorbusch K, Zimic M, Gutierrez A, Decuypere S, Vanaerschot M, De-Doncker S, Maes L, Llanos-Cuentas A, Chappuis F, Arevalo J, Dujardin JC (2010) Comparison of gene expression patterns among Leishmania braziliensis clinical isolates showing a different in vitro susceptibility to pentavalent antimony. Parasitology 3:1–11Google Scholar
  4. Ainsworth N, Cooke JA, Johnson MS (1990) Distribution of antimony in contaminated grassland: 2—small mammals and invertebrates. Environ Pollut 65:79–87PubMedCrossRefGoogle Scholar
  5. Ait-Oudhia K, Gazanion E, Oury B, Vergnes B, Sereno D (2011) The fitness of antimony-resistant Leishmania parasites: lessons from the field. Trends Parasitol 4:141–142CrossRefGoogle Scholar
  6. Akopyants NS, Kimblin N, Secundino N, Patrick R, Peters N, Lawyer P, Dobson DE, Beverley SM, Sacks DL (2009) Demonstration of genetic exchange during cyclical development of Leishmania in the sand fly vector. Science 324:265–268PubMedCrossRefGoogle Scholar
  7. Anderson T, Nkhoma N, Ecker A, Fidock D (2010) How can we identify parasite genes that underlie antimalarial drug resistance? Pharmacogenomics 12:59–85CrossRefGoogle Scholar
  8. Antoniou M, Doulgerakis C, Pratlong F, Dedet JP, Tselentis Y (2004) Treatment failure due to mixed infection by different strains of the parasite Leishmania infantum. Am J Trop Med Hyg 71:71–72PubMedGoogle Scholar
  9. Ashutosh S, Sundar N, Goyal N (2007) Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 56:143–153PubMedCrossRefGoogle Scholar
  10. Berman JD (1984) Leishmania tropica: quantitation of in vitro activity of antileishmanial agents by Giemsa staining, viability, and 3H-formycin B incorporation. J Parasitol 70:561–562PubMedCrossRefGoogle Scholar
  11. Berman JD, Gallalee JV, Best JM (1987) Sodium stibogluconate (Pentostam) inhibition of glucose catabolism via the glycolytic pathway, and fatty acid beta-oxidation in Leishmania mexicana amastigotes. Biochem Pharmacol 3:197–201Google Scholar
  12. Berman JD, Edwards N, King M, Grogl M (1989) Biochemistry of Pentostam resistant Leishmania. Am J Trop Med Hyg 40:159–164PubMedGoogle Scholar
  13. Bhagure GR, Mirgane SR (2011) Heavy metal concentrations in groundwaters and soils of Thane Region of Maharashtra, India. Environ Monit Assess 173:643–652PubMedCrossRefGoogle Scholar
  14. Blower SM, Small PM, Hopewell PC (1996) Control strategies for tuberculosis epidemics: new models for old problems. Science 273:497–500PubMedCrossRefGoogle Scholar
  15. Bocedi A, Dawood KF, Fabrini R, Federici G, Gradoni L, Pedersen JZ, Ricci G (2010) Trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites. FASEB J 24:1035–1042PubMedCrossRefGoogle Scholar
  16. Bueding E, Mansour JM (1957) The relationship between inhibition of phosphofructokinase activity and the mode of action of trivalent organic antimonials on Schistosoma mansoni. Br J Pharmacol Chemother 12:159–165PubMedGoogle Scholar
  17. Carter KC, Hutchison S, Boitelle A, Murray HW, Sundar S, Mullen AB (2005) Sodium stibogluconate resistance in Leishmania donovani correlates with greater tolerance to macrophage antileishmanial responses and trivalent antimony therapy. Parasitology 131:747–757PubMedCrossRefGoogle Scholar
  18. Carter KC, Hutchison S, Henriquez FL, Légaré D, Ouellette M, Roberts CW, Mullen AB (2006) Resistance of Leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase. Antimicrob Agents Chemother 50:88–95PubMedCrossRefGoogle Scholar
  19. Choudhury K, Zander D, Kube M, Reinhardt R, Clos J (2008) Identification of a Leishmania infantum gene mediating resistance to miltefosine and SbIII. Int J Parasitol 38:1411–1423PubMedCrossRefGoogle Scholar
  20. Croft SL (2001) Monitoring drug resistance in leishmaniasis. Trop Med Int Health 6:899–905PubMedCrossRefGoogle Scholar
  21. Croft SL, Seifert K, Yardley V (2006a) Current scenario of drug development for leishmaniasis. Indian J Med Res 123:399–410PubMedGoogle Scholar
  22. Croft SL, Sundar S, Fairlamb AH (2006b) Drug resistance in leishmaniasis. Clin Microbiol Rev 19:111–126PubMedCrossRefGoogle Scholar
  23. Cunningham ML, Fairlamb AH (1995) Trypanothione reductase from Leishmania donovani. Purification, characterisation and inhibition by trivalent antimonials. Eur J Biochem 230:460–468PubMedCrossRefGoogle Scholar
  24. De La Llave E, Lecoeur H, Besse A, Milon G, Prina E, Lang T (2011) A combined luciferase imaging and reverse transcription polymerase chain reaction assay for the study of Leishmania amastigote burden and correlated mouse tissue transcript fluctuations. Cell Microbiol 13:81–91CrossRefGoogle Scholar
  25. Demicheli C, Frézard F, Mangrum JB, Farrell NP (2008) Interaction of trivalent antimony with a CCHC zinc finger domain: potential relevance to the mechanism of action of antimonial drugs. Chem Commun (Camb) 39:4828–4830CrossRefGoogle Scholar
  26. Denton H, McGregor JC, Coombs GH (2004) Reduction of anti-leishmanial pentavalent antimonial drugs by a parasite-specific thiol-dependent reductase, TDR1. Biochem 381:405–412CrossRefGoogle Scholar
  27. Fairlamb AH, Cerami A (1992) Metabolism and functions of trypanothione in the Kinetoplastida. Annu Rev Microbiol 46:695–729PubMedCrossRefGoogle Scholar
  28. Faraut-Gambarelli F, Piarroux R, Deniau M, Giusiano B, Marty P, Michel G, Faugère B, Dumon H (1997) In vitro and in vivo resistance of Leishmania infantum to meglumine antimoniate: a study of 37 strains collected from patients with visceral leishmaniasis. Antimicrob Agents Chemother 41:827–830PubMedGoogle Scholar
  29. Gambarelli F, Franck J, Dumon H (1987) Sensibilité des Leishmania spp aux derives stibiès. Utilisation de macrophages péritonéaux de souris. Ann Soc Belge Med Trop 67:149–155Google Scholar
  30. Gebre-Hiwot A, Tadesse G, Croft SL, Frommel D (1992) An in vitro model for screening antileishmanial drugs: the human leukaemia monocyte cell line, THP-1. Acta Trop 51:237–245PubMedCrossRefGoogle Scholar
  31. Genest PA, Haimeur A, Légaré D, Sereno D, Roy G, Messier N, Papadopoulou B, Ouellette M (2008) A protein of the leucine-rich repeats (LRRs) superfamily is implicated in antimony resistance in Leishmania infantum amastigotes. Mol Biochem Parasitol 158:95–99PubMedCrossRefGoogle Scholar
  32. Goodwin LG (1995) Pentostam (sodium stibogluconate); a 50-year personal réminiscence. Trans R Soc Trop Med Hyg 89:39–341CrossRefGoogle Scholar
  33. Gourbal B, Sonuc N, Bhattacharjee H, Légaré D, Sundar S, Ouellette M, Rosen BP, Mukhopadhyay R (2004) Drug uptake and modulation of drug resistance in Leishmania by an aquaglyceroporin. J Biol Chem 279:31010–31017PubMedCrossRefGoogle Scholar
  34. Goyeneche-Patino DA, Valderrama L, Walker J, Saravia NG (2008) Antimony resistance and trypanothione in experimentally selected and clinical strains of Leishmania panamensis. Antimicrob Agents Chemother 52:4503–4506PubMedCrossRefGoogle Scholar
  35. Grondin K, Haimeur A, Mukhopadhyay R, Rosen BP, Ouellette M (1997) Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J 16:3057–3065PubMedCrossRefGoogle Scholar
  36. Guimond C, Trudel N, Brochu C, Marquis N, El-Fadili A, Peytavi R, Briand G, Richard D, Messier N, Papadopoulou B, Corbeil J, Bergeron MG, Légaré D, Ouellette M (2003) Modulation of gene expression in Leishmania drug resistant mutants as determined by targeted DNA microarrays. Nucleic Acids Res 31:5886–5896PubMedCrossRefGoogle Scholar
  37. Gupta N, Goyal N, Rastogi AK (2001) In vitro cultivation and characterization of axenic amastigotes of Leishmania. Trends Parasitol 17:150–153PubMedCrossRefGoogle Scholar
  38. Hadighi R, Mohebali M, Boucher P, Hajjaran H, Khamesipour A, Ouellette M (2006) Unresponsiveness to Glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites. PLoS Med 3:e162PubMedCrossRefGoogle Scholar
  39. Haimeur A, Guimond C, Pilote S, Mukhopadhyay R, Rosen BP, Poulin R, Ouellette M (1999) Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite-resistant Leishmania. Mol Microbiol 34:726–735PubMedCrossRefGoogle Scholar
  40. Haldar AK, Yadav V, Singhal E, Bisht KK, Singh A, Bhaumik S, Basu R, Sen P, Roy S (2010) Leishmania donovani isolates with antimony-resistant but not sensitive phenotype inhibit sodium antimony gluconate-induced dendritic cell activation. PLoS Pathog 6:e1000907PubMedCrossRefGoogle Scholar
  41. Holzmuller P, Sereno D, Lemesre JL (2005) Lower nitric oxide susceptibility of trivalent antimony-resistant amastigotes of Leishmania infantum. Antimicrob Agents Chemother 49:4406–4409PubMedCrossRefGoogle Scholar
  42. Krachler M, Zheng J, Koerner R, Zdanowicz C, Fisher D, Shotyk W (2005) Increasing atmospheric antimony contamination in the northern hemisphere: snow and ice evidence from Devon Island, Arctic Canada. J Environ Monit 7:169–1176CrossRefGoogle Scholar
  43. Kumar D, Kulshrestha A, Singh R, Salotra P (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 53:835–838PubMedCrossRefGoogle Scholar
  44. Kumar A, Sisodia B, Misra P, Sundar S, Shasany AK, Dube A (2010) Proteome mapping of overexpressed membrane-enriched and cytosolic proteins in sodium antimony gluconate (SAG) resistant clinical isolate of Leishmania donovani. Br J Clin Pharmacol 70:609–617PubMedCrossRefGoogle Scholar
  45. Lachaud L, Bourgeois N, Plourde M, Leprohon P, Bastien P, Ouellette M (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–e22PubMedCrossRefGoogle Scholar
  46. Lang T, Lecoeur H, Prina E (2009) Imaging Leishmania development in their host cells. Trends Parasitol 25:464–473PubMedCrossRefGoogle Scholar
  47. Légaré D, Richard D, Mukhopadhyay R, Stierhof YD, Rosen BP, Haimeur A, Papadopoulou B, Ouellette M (2001) The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J Biol Chem 276:26301–26307PubMedCrossRefGoogle Scholar
  48. Leprohon P, Légaré D, Ouellette M (2009a) Intracellular localization of the ABCC proteins of Leishmania and their role in resistance to antimonials. Antimicrob Agents Chemother 53:2646–26499PubMedCrossRefGoogle Scholar
  49. Leprohon P, Légaré D, Raymond F, Madore E, Hardiman G, Corbeil J, Ouellette M (2009b) Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum. Nucleic Acids Res 37:1387–1399PubMedCrossRefGoogle Scholar
  50. Liarte DB, Murta SM (2010) Selection and phenotype characterization of potassium antimony tartrate-resistant populations of four new world Leishmania species. Parasitol Res 107:205–212PubMedCrossRefGoogle Scholar
  51. Lira R, Sundar S, Makharia A, Kenney R, Gam A, Saraiva E, Sacks D (1999) Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony-resistant strains of Leishmania donovani. J Infect Dis 180:564–567PubMedCrossRefGoogle Scholar
  52. Llanos-Cuentas A, Tulliano G, Araujo-Castillo R, Miranda-Verastegui C, Santamaria-Castrellon G, Ramirez L, Lazo M, De-Doncker S, Boelaert M, Robays J, Dujardin JC, Arevalo J, Chappuis F (2008) Clinical and parasite species risk factors for pentavalent antimonial treatment failure in cutaneous leishmaniasis in Peru. Clin Infect Dis 46:223–231PubMedCrossRefGoogle Scholar
  53. Maharjan M, Singh S, Chatterjee M, Madhubala R (2008) Role of aquaglycoprotein (AQP-1) gene and drug uptake in antimony-resistant isolates of Leishmania donovani. Am J Trop Med Hyg 79:69–75PubMedGoogle Scholar
  54. Mandal G, Wyllie S, Singh N, Sundar S, Fairlamb AH, Chatterjee M (2007) Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony. Parasitology 134:1679–1687PubMedCrossRefGoogle Scholar
  55. Mandal S, Maharjan M, Singh S, Chatterjee M, Madhubala R (2010) Assessing aquaglyceroporin gene status and expression profile in antimony-susceptible and resistant clinical isolates of Leishmania donovani from India. J Antimicrob Chemother 65:496–507PubMedCrossRefGoogle Scholar
  56. Marquis N, Gourbal B, Rosen BP, Mukhopadhyay R, Ouellette M (2005) Modulation in aquaglyceroporin AQP1 gene transcript levels in drug-resistant Leishmania. Mol Microbiol 57:1690–1699PubMedCrossRefGoogle Scholar
  57. Mittal MK, Rai S, Ravinder A, Gupta S, Sundar S, Goyal N (2007) Characterization of natural antimony résistance in Leishmania donovani isolates. Am J Trop Med Hyg 76:681–688PubMedGoogle Scholar
  58. Mondal S, Bhattacharya P, Ali N (2010) Current diagnosis and treatment of visceral leishmaniasis. Expert Rev Anti Infect Ther 8:919–944PubMedCrossRefGoogle Scholar
  59. Monte-Neto RL, Coelho AC, Raymond F, Légaré D, Corbeil J, Melo MN, Frézard F, Ouellette M (2011) Gene expression profiling and molecular characterization of antimony resistance in Leishmania amazonensis. PLoS Negl Trop Dis 5:e1167PubMedCrossRefGoogle Scholar
  60. Mookerjee-Basu J, Mookerjee A, Sen P, Bhaumik S, Sen P, Banerjee S, Naskar K, Choudhuri SK, Saha B, Raha S, Roy S (2006) Sodium antimony gluconate induces generation of reactive oxygen species and nitric oxide via phosphoinositide 3-kinase and mitogen-activated protein kinase activation in Leishmania donovani-infected macrophages. Antimicrob Agents Chemother 50:1788–1797PubMedCrossRefGoogle Scholar
  61. Mukherjee A, Padmanabhan PK, Singh S, Roy G, Girard I, Chatterjee M, Ouellette M, Madhubala R (2007) Role of ABC transporter MRPA, gamma-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. J Antimicrob Chemother 59:204–211PubMedCrossRefGoogle Scholar
  62. Murray MW (2010) Treatment of visceral leishmaniasis in 2010: direction from Bihar state, India. Future Microbiol 5:1301–1303PubMedCrossRefGoogle Scholar
  63. Natera S, Machuca C, Padren-Nieves M, Romero A, Diaz E, Ponte-Sucre A (2007) Leishmania spp.: proficiency of drug-resistant parasites. Int J Antimicrob Agents 29:637–642PubMedCrossRefGoogle Scholar
  64. Ouellette M, Légaré D, Haimeur A, Grondin K, Roy G, Brochu C, Papadopoulou B (1998) ABC transporters in Leishmania and their role in drug resistance. Drug Resist Update 1:43–48CrossRefGoogle Scholar
  65. Oza SL, Tetaud E, Ariyanayagam MR, Warnon SS, Fairlamb AH (2002) A single enzyme catalyses formation of trypanothione from glutathione and spermidine in Trypanosoma cruzi. J Biol Chem 277:35853–35861PubMedCrossRefGoogle Scholar
  66. Robledo SM, Valencia AZ, Saravia NG (1999) Sensitivity to Glucantime of Leishmania viannia isolated from patients prior to treatment. J Parasitol 85:360–366PubMedCrossRefGoogle Scholar
  67. Rosen BP (1995) Resistance mechanisms to arsenicals and antimonials. J Basic Clin Physio Pharmacol 6:251–263CrossRefGoogle Scholar
  68. Santos DO, Coutinho CE, Madeira MF, Bottino CG, Vieira RT, Nascimento SB, Bernardino A, Bourguignon SC, Corte-Real S, Pinho RT, Rodrigues CR, Castro HC (2008) Leishmaniasis treatment—a challenge that remains: a review. Parasitol Res 103:1–10PubMedCrossRefGoogle Scholar
  69. Sarkar A, Saha P, Mandal G, Mukhopadhyay D, Roy S, Singh SK, Das S, Goswami RP, Saha B, Kumar D, Das P, Chatterjee M (2011) Monitoring of intracellular nitric oxide in leishmaniasis: its applicability in patients with visceral leishmaniasis. Cytometry 79:35–45PubMedCrossRefGoogle Scholar
  70. Seifert K, Escobar P, Croft SL (2010) In vitro activity of anti-leishmanial drugs against Leishmania donovani is host cell dependent. J Antimicrob Chemother 65:508–511PubMedCrossRefGoogle Scholar
  71. Sereno D, Lemesre JL (1997) Use of an enzymatic micromethod to quantify amastigote stage of Leishmania amazonensis in vitro. Parasitol Res 83:401–403PubMedCrossRefGoogle Scholar
  72. Sereno D, Cordeiro da Silva A, Mathieu-Daude F, Ouaissi A (2007) Advances and perspectives in Leishmania cell based drug-screening procedures. Parasitol Int 56:3–7PubMedCrossRefGoogle Scholar
  73. Shotyk W, Krachler M, Chen B (2005a) Antimony: global environmental contaminant. J Environ Monit 7:1135–1136PubMedCrossRefGoogle Scholar
  74. Shotyk W, Krachler M, Chen B, Zheng J (2005b) Natural abundance of Sb and Sc in pristine groundwaters, Springwater township, Ontario, Canada, and implications for tracing contamination from landfill leachates. J Environ Monit 7:1238–1244PubMedCrossRefGoogle Scholar
  75. Singh R, Kumar D, Duncan RC, Nakhasi HL, Salotra P (2010) Overexpression of histone H2A modulates drug susceptibility in Leishmania parasites. Int J Antimicrob Agents 36:50–57PubMedCrossRefGoogle Scholar
  76. Souza AS, Giudice A, Pereira JM, Guimaraes LM, De-Jesus AR, De-Moura TR, Wilson ME, Carvalho EM, Almeida RP (2010) Resistance of Leishmania (Viannia) braziliensis to nitric oxide: correlation with antimony therapy and TNF-alpha production. BMC Infect Dis 10:209PubMedCrossRefGoogle Scholar
  77. Sundar S, Pai K, Kumar R, Pathak-Tripathi K, Gam AA, Ray M, Kenney RT (2001) Resistance to treatment in kala-azar: speciation of isolates from northeast India. Am J Trop Med Hyg 65:193–196PubMedGoogle Scholar
  78. t'Kindt R, Scheltema RA, Jankevics A, Brunker K, Rijal S, Dujardin JC, Breitling R, Watson DG, Coombs GH, Decuyper S (2010) Metabolomics to unveil and understand phenotypic diversity between pathogen populations. PLoS Negl Trop Dis 4:e904PubMedCrossRefGoogle Scholar
  79. Torres DC, Adaui V, Ribeiro-Alves M, Romero GA, Arévalo J, Cupolillo E, Dujardin JC (2010) Targeted gene expression profiling in Leishmania braziliensis and Leishmania guyanensis parasites isolated from Brazilian patients with different antimonial treatment outcomes. Infect Genet Evol 10:727–733PubMedCrossRefGoogle Scholar
  80. Ubeda JM, Légaré D, Raymond F, Ouameur AA, Boisvert S, Rigault P, Corbeil J, Tremblay MJ, Olivier M, Papadopoulou B, Ouellette M (2008) Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biol 9:R115PubMedCrossRefGoogle Scholar
  81. Vanaerschot M, Maes L, Ouakad M, Adaui V, Maes L, De Doncker S, Rijal S, Chappuis F, Dujardin JC, Decuypere S (2010) Linking in vitro and in vivo survival of clinical Leishmania donovani strains. PLoS One 5:e12211PubMedCrossRefGoogle Scholar
  82. Vanlerberghe V, Diap G, Guerin JP, Meheus F, Gerstl S, Van der Stuyft P, Boelaert M (2007) Drug policy for visceral leishmaniasis: a cost-effectiveness analysis. Trop Med Int Health 12:274–283PubMedCrossRefGoogle Scholar
  83. Vergnes B, Gourbal B, Girard I, Sundar S, Drummelsmith J, Ouellette M (2007) A proteomics screen implicates HSP83 and a small kinetoplastid calpain-related protein in drug resistance in Leishmania donovani clinical field isolates by modulating drug-induced programmed cell death. Mol Cell Proteomics 6:88–101PubMedGoogle Scholar
  84. Vermeersch M, da Luz RI, Toté K, Timmermans JP, Cos P, Maes L (2009) In vitro susceptibilities of Leishmania donovani promastigote and amastigote stages to antileishmanial reference drugs: practical relevance of stage-specific differences. Antimicrob Agents Chemother 53:3855–3859PubMedCrossRefGoogle Scholar
  85. Walker J, Saravia NG (2004) Inhibition of Leishmania donovani promastigote DNA topoisomerase I and human monocyte DNA topoisomerases I and II by antimonial drugs and classical antitopoisomerase agents. J Parasitol 90:1155–62Google Scholar
  86. Wilson PE, Alker AP, Meshnick SR (2005) Real-time PCR methods for monitoring antimalarial drug resistance. Trends Parasitol 21:278–283PubMedCrossRefGoogle Scholar
  87. Wyllie S, Cunningham ML, Fairlamb AH (2004) Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. J Biol Chem 279:39925–39932PubMedCrossRefGoogle Scholar
  88. Wyllie S, Vickers TJ, Fairlamb AH (2008) Roles of trypanothione S-transferase and tryparedoxin peroxidase in resistance to antimonials. Antimicrob Agents Chemother 52:359–365CrossRefGoogle Scholar
  89. Wyllie S, Mandal G, Singh N, Sundar S, Fairlamb AH, Chatterjee M (2010) Elevated levels of tryparedoxin peroxidase in antimony unresponsive Leishmania donovani field isolates. Mol Biochem Parasitol 173:162–164PubMedCrossRefGoogle Scholar
  90. Yardley V, Ortuno N, Llanos-Cuentas A, Chappuis F, Doncker SD, Ramirez L, Croft S, Arevalo J, Adaui V, Bermudez H, Decuypere S, Dujardin JC (2006) American tegumentary leishmaniasis: is antimonial treatment outcome related to parasite drug susceptibility? J Infect Dis 194:1168–1175PubMedCrossRefGoogle Scholar
  91. Zhou Y, Messier N, Ouellette M, Rosen BP, Mukhopadhyay R (2004) Leishmania major LmACR2 is a pentavalent antimony reductase that confer sensitivity to the drug Pentostam. J Biol Chem 279:37445–37451PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Khatima Aït-Oudhia
    • 3
  • Elodie Gazanion
    • 2
  • Baptiste Vergnes
    • 2
  • Bruno Oury
    • 2
  • Denis Sereno
    • 1
  1. 1.MIVEGEC (UM1-CNRS 5290-IRD 224), Département SantéReprésentation IRD au MarocRabatMorocco
  2. 2.MIVEGEC (UM1-CNRS 5290-IRD 224)Institut de Recherche pour le Développement (IRD)Montpellier Cedex 5France
  3. 3.Ecole Nationale Supérieure Vétérinaire d’AlgerAlgerAlgeria

Personalised recommendations