Skip to main content

The Role of Proteomics in the Study of Drug Resistance

  • Chapter
  • First Online:
Drug Resistance in Leishmania Parasites

Abstract

The recent completion of the genomic sequencing of three species of Leishmania, L. (L.) major, L. (L.) infantum, and L. (V.) braziliensis has enormous relevance to the study of the leishmaniasis pathogenesis. However, since in Leishmania the control of gene expression relies on the stability or processing of the mature mRNA, as well as on the posttranslational modifications of proteins, the genomic sequences alone are insufficient to predict protein expression within the parasites. In this scenario, proteomic technologies provide feasible pathways to functional studies of this parasite. With the challenging increase of natural drug resistance by Leishmania, the combination of the available genomic resources of these parasites with powerful high-throughput proteomic analysis is urgently needed to shed light on resistance mechanisms and identify new drug targets against Leishmania. Diverse proteomic approaches have been used to describe and catalogue global protein profiles of Leishmania spp. reveal changes in protein expression during development, determine the subcellular localization of gene products, evaluate host-parasite interactions, and elucidate drug resistance mechanisms. The characterization of these proteins has advanced, although many fundamental questions remain unanswered. Here we discuss the recent proteomic discoveries that have contributed to the understanding of drug resistance mechanisms in Leishmania parasites.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ivens AC, Peacock CS, Worthey EA, Murphy L, et al. The genome of the kinetoplastid parasite, Leishmania major. Science. 2005;309:436–42.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Peacock CS, Seeger K, Harris D, Murphy L, et al. Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nat Genet. 2007;39:839–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Imamura H, Downing T, Van den Broeck F, Sanders MJ, et al. Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent. Elife. 2016;5:e12613.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev. 2006;19:111–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Faraut-Gambarelli F, Piarroux R, Deniau M, Giusiano B, et al. 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. 1997;41:827–30.

    PubMed  PubMed Central  CAS  Google Scholar 

  6. Lira R, Sundar S, Makharia A, Kenney R, et al. Evidence that the high incidence of treatment failures in Indian kalaazar is due to the emergence of antimony-resistant strains of Leishmania donovani. J Infect Dis. 1999;180:564–7.

    Article  PubMed  CAS  Google Scholar 

  7. Palacios R, Osorio LE, Grajalew LF, Ochoa MT. Treatment failure in children in a randomized clinical trial with 10 and 20 days of meglumine antimonate for cutaneous leishmaniasis due to Leishmania Viannia species. Am J Trop Med Hyg. 2001;64:187–93.

    Article  PubMed  CAS  Google Scholar 

  8. Sundar S. Drug resistance in Indian visceral leishmaniasis. Trop Med Int Health. 2001;6:849–54.

    Article  PubMed  CAS  Google Scholar 

  9. Abdo MG, Elamin WM, Khalil EA, Mukhtar MM. Antimony-resistant Leishmania donovani in eastern Sudan: incidence and in vitro correlation. East Mediterr Health J. 2003;9:837–43.

    PubMed  CAS  Google Scholar 

  10. Das VN, Ranjan A, Bimal S, Siddique NA, et al. Magnitude of unresponsiveness to sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar. Natl Med J India. 2005;18:131–3.

    PubMed  CAS  Google Scholar 

  11. Hadighi R, Mohebali M, Boucher P, Hajjaran H, et al. Unresponsiveness to Glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites. PLoS Med. 2006;3:e162.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Rojas R, Valderrama L, Valderrama M, Varona MX, et al. Resistance to antimony and treatment failure in human Leishmania (Viannia) infection. J Infect Dis. 2006;193:1375–83.

    Article  PubMed  CAS  Google Scholar 

  13. Holzer TR, McMaster WR, Forney JD. Expression profiling by whole-genome interspecies microarray hybridization reveals differential gene expression in procyclic promastigotes, lesion-derived amastigotes, and axenic amastigotes in Leishmania mexicana. Mol Biochem Parasitol. 2006;146:198–218.

    Article  PubMed  CAS  Google Scholar 

  14. Leifso K, Cohen-Freue G, Dogra N, Murray A, et al. Genomic and proteomic expression analysis of Leishmania promastigote and amastigote life stages: the Leishmania genome is constitutively expressed. Mol Biochem Parasitol. 2007;152:35–46.

    Article  PubMed  CAS  Google Scholar 

  15. Cohen-Freue G, Holzer TR, Forney JD, McMaster WR. Global gene expression in Leishmania. Int J Parasitol. 2007;37:1077–86.

    Article  PubMed  CAS  Google Scholar 

  16. El-Sayed NM, Myler PJ, Blandin G, Berriman M, et al. Comparative genomics of trypanosomatid parasitic protozoa. Science. 2005;309:404–9.

    Article  PubMed  CAS  Google Scholar 

  17. Rogers MB, Hilley JD, Dickens NJ, Wilkes J, et al. Chromosome and gene copy number variation allow major structural change between species and strains of Leishmania. Genome Res. 2011;21:2129–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Fiebig M, Kelly S, Gluenz E. Comparative life cycle transcriptomics revises Leishmania mexicana genome annotation and links a chromosome duplication with parasitism of vertebrates. PLoS Pathog. 2015;11:e1005186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Ubeda JM, Légaré D, Raymond F, Ouameur AA, et al. Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biol. 2008;9:R115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Leprohon P, Légaré D, Raymond F, Hardiman G, et al. Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum. Nucleic Acids Res. 2009;37:1387–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Downing T, Imamura H, Decuypere S, Clark TG, et al. Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance. Genome Res. 2011;21:2143–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Mannaert A, Downing T, Imamura H, Dujardin JC. Adaptive mechanisms in pathogens: universal aneuploidy in Leishmania. Trends Parasitol. 2012;28:370–6.

    Article  PubMed  CAS  Google Scholar 

  23. Clayton C, Shapira M. Post-transcriptional regulation of gene expression in trypanosomes and leishmanias. Mol Biochem Parasitol. 2007;156:93–101.

    Article  PubMed  CAS  Google Scholar 

  24. Haile S, Papadopoulou B. Developmental regulation of gene expression in trypanosomatid parasitic protozoa. Curr Opin Microbiol. 2007;10:569–77.

    Article  PubMed  CAS  Google Scholar 

  25. Lee MG, Atkinson BL, Giannini SH, Van der Ploeg LH. Structure and expression of the hsp 70 gene family of Leishmania major. Nucleic Acids Res. 1988;16:9567–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Quijada L, Soto M, Alonso C, Requena JM. Analysis of post-transcriptional regulation operating on transcription products of the tandemly linked Leishmania infantum hsp70 genes. J Biol Chem. 1997;272:4493–9.

    Article  PubMed  CAS  Google Scholar 

  27. Holzer TR, Mishra KK, LeBowitz JH, Forney JD. Coordinate regulation of a family of promastigote-enriched mRNAs by the 3′UTR PRE element in Leishmania mexicana. Mol Biochem Parasitol. 2008;157:54–64.

    Article  PubMed  CAS  Google Scholar 

  28. Saxena A, Lahav T, Holland N, Aggarwal G, et al. Analysis of the Leishmania donovani transcriptome reveals an ordered progression of transient and permanent changes in gene expression during differentiation. Mol Biochem Parasitol. 2007;152:53–65.

    Article  PubMed  CAS  Google Scholar 

  29. Almeida R, Gilmartin BJ, McCann SH, Norrish A, et al. Expression profiling of the Leishmania life cycle: cDNA arrays identify developmentally regulated genes present but not annotated in the genome. Mol Biochem Parasitol. 2004;136:87–100.

    Article  PubMed  CAS  Google Scholar 

  30. Akopyants NS, Matlib RS, Bukanova EN, Smeds MR, et al. Expression profiling using random genomic DNA microarrays identifies differentially expressed genes associated with three major developmental stages of the protozoan parasite Leishmania major. Mol Biochem Parasitol. 2004;136:71–86.

    Article  PubMed  CAS  Google Scholar 

  31. Rochette A, Raymond F, Ubeda JM, Smith M, et al. Genome-wide gene expression profiling analysis of Leishmania major and Leishmania infantum developmental stages reveals substantial differences between the two species. BMC Genomics. 2008;9:255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Guimond C, Trudel N, Brochu C, Marquis N, et al. Modulation of gene expression in Leishmania drug resistant mutants as determined by targeted DNA microarrays. Nucleic Acids Res. 2003;31:5886–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Quijada L, Soto M, Requena JM. Genomic DNA macroarrays as a tool for analysis of gene expression in Leishmania. Exp Parasitol. 2005;111:64–70.

    Article  PubMed  CAS  Google Scholar 

  34. Depledge DP, Evans KJ, Ivens AC, Aziz N, et al. Comparative expression profiling of Leishmania: modulation in gene expression between species and in different host genetic backgrounds. PLoS Negl Trop Dis. 2009;3:e476.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Leprohon P, Légaré D, Girard I, Papadopoulou B, et al. Modulation of Leishmania ABC protein gene expression through life stages and among drug-resistant parasites. Eukaryot Cell. 2006;5:1713–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. McNicoll F, Drummelsmith J, Müller M, Madore E, et al. A combined proteomic and transcriptomic approach to the study of stage differentiation in Leishmania infantum. Proteomics. 2006;6:3567–81.

    Article  PubMed  CAS  Google Scholar 

  37. Walther TC, Mann M. Mass spectrometry-based proteomics in cell biology. J Cell Biol. 2010;190:491–500.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Karas M, Hillemkamp F. Laser desorption ionization of proteins with molecular masses exceeding 10000 kDa. Anal Chem. 1988;60:2299–301.

    Article  PubMed  CAS  Google Scholar 

  39. Tanaka K, Waki H, Ido Y, Akita S, et al. Protein and polymer analyses up to m/z 100000 by laser ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom. 1988;2:151–3.

    Article  CAS  Google Scholar 

  40. Fenn J, Mann M, Meng CK, Wong SF, et al. Electrospray ionization for mass spectrometry of large biomolecules. Science. 1989;246:64–71.

    Article  PubMed  CAS  Google Scholar 

  41. Cuervo P, Domont GB, De Jesus JB. Proteomics of trypanosomatids of human medical importance. J Proteomics. 2010;73:845–67.

    Article  PubMed  CAS  Google Scholar 

  42. Paape D, Aebischer T. Contribution of proteomics of Leishmania spp. to the understanding of differentiation, drug resistance mechanisms, vaccine and drug development. J Proteomics. 2011;74:1614–24.

    Article  PubMed  CAS  Google Scholar 

  43. Paape D, Barrios-Llerena ME, Le BT, Mackay L, et al. Gel free analysis of the proteome of intracellular Leishmania mexicana. Mol Biochem Parasitol. 2010;169:108–14.

    Article  PubMed  CAS  Google Scholar 

  44. Tsigankov P, Gherardini PF, Helmer-Citterich M, Späth GF, et al. Phosphoproteomic analysis of differentiating Leishmania parasites reveals a unique stage-specific phosphorylation motif. J Proteome Res. 2013;12:3405–12.

    Article  PubMed  CAS  Google Scholar 

  45. Braga MS, Neves LX, Campos JM, Roatt BM, et al. Shotgun proteomics to unravel the complexity of the Leishmania infantum exoproteome and the relative abundance of its constituents. Mol Biochem Parasitol. 2014;195:43–53.

    Article  PubMed  CAS  Google Scholar 

  46. Pawar H, Sahasrabuddhe NA, Renuse S, Keerthikumar S, et al. A proteogenomic approach to map the proteome of an unsequenced pathogen - Leishmania donovani. Proteomics. 2012;12:832–44.

    Article  PubMed  CAS  Google Scholar 

  47. Pescher P, Blisnick T, Bastin P, Spath GF. Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation. Cell Microbiol. 2011;13:978–91.

    Article  PubMed  CAS  Google Scholar 

  48. Biyani N, Madhubala R. Quantitative proteomic profiling of the promastigotes and the intracellular amastigotes of Leishmania donovani isolates identifies novel proteins having a role in Leishmania differentiation and intracellular survival. Biochim Biophys Acta. 2012;1824:1342–50.

    Article  PubMed  CAS  Google Scholar 

  49. Sardar AH, Kumar S, Kumar A, Purkait B, et al. Proteome changes associated with Leishmania donovani promastigote adaptation to oxidative and nitrosative stresses. J Proteomics. 2013;81:185–99.

    Article  PubMed  CAS  Google Scholar 

  50. Singh AK, Roberts S, Ullman B, Madhubala R. A quantitative proteomic screen to identify potential drug resistance mechanism in alpha-difluoromethylornithine (DFMO) resistant Leishmania donovani. J Proteomics. 2014;102:44–59.

    Article  PubMed  CAS  Google Scholar 

  51. Tsigankov P, Gherardini PF, Helmer-Citterich M, Späth GF, et al. Regulation dynamics of Leishmania differentiation: deconvoluting signals and identifying phosphorylation trends. Mol Cell Proteomics. 2014;13:1787–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Zilberstein D. Proteomic analysis of posttranslational modifications using iTRAQ in Leishmania. Methods Mol Biol. 2015;1201:261–8.

    Article  PubMed  CAS  Google Scholar 

  53. Wyllie S, Roberts AJ, Norval S, Patterson S, et al. Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in Leishmania. PLoS Pathog. 2016;12:e1005971.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Acestor N, Masina S, Walker J, Saravia NG, et al. Establishing two-dimensional gels for the analysis of Leishmania proteomes. Proteomics. 2002;2:877–9.

    Article  PubMed  CAS  Google Scholar 

  55. Góngora R, Acestor N, Quadroni M, Fasel N, et al. Mapping the proteome of Leishmania Viannia parasites using two-dimensional polyacrylamide gel electrophoresis and associated technologies. Biomédica. 2003;23:153–60.

    Article  PubMed  Google Scholar 

  56. Drummelsmith J, Brochu V, Girard I, Messier N, et al. Proteome mapping of the protozoan parasite Leishmania and application to the study of drug targets and resistance mechanisms. Mol Cell Proteomics. 2003;2:146–55.

    Article  PubMed  CAS  Google Scholar 

  57. Brobey RK, Mei FC, Cheng X, Soong L. Comparative two-dimensional gel electrophoresis maps for promastigotes of Leishmania amazonensis and Leishmania major. Braz J Infect Dis. 2006;10:1–6.

    Article  PubMed  Google Scholar 

  58. Brobey RK, Soong L. Establishing a liquid-phase IEF in combination with 2-DE for the analysis of Leishmania proteins. Proteomics. 2007;7:116–20.

    Article  PubMed  CAS  Google Scholar 

  59. Cuervo P, de Jesus JB, Junqueira M, Mendonça-Lima L, et al. Proteome analysis of Leishmania (Viannia) braziliensis by two-dimensional gel electrophoresis and mass spectrometry. Mol Biochem Parasitol. 2007;154:6–21.

    Article  PubMed  CAS  Google Scholar 

  60. Costa MM, Andrade HM, Bartholomeu DC, Freitas LM, et al. Analysis of Leishmania chagasi by 2-D difference gel electrophoresis (2-D DIGE) and immunoproteomic: identification of novel candidate antigens for diagnostic tests and vaccine. J Proteome Res. 2011;10:2172–84.

    Article  PubMed  CAS  Google Scholar 

  61. Aebischer T. Leishmania spp. proteome data sets: a comprehensive resource for vaccine development to target visceral leishmaniasis. Front Immunol. 2014;5:260.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. da Fonseca Pires S, Fialho LC Jr, Silva SO, Melo MN, et al. Identification of virulence factors in Leishmania infantum strains by a proteomic approach. J Proteome Res. 2014;13:1860–72.

    Article  PubMed  CAS  Google Scholar 

  63. McCall LI, Zhang WW, Dejgaard K, Atayde VD, et al. Adaptation of Leishmania donovani to cutaneous and visceral environments: in vivo selection and proteomic analysis. J Proteome Res. 2015;14:1033–59.

    Article  PubMed  CAS  Google Scholar 

  64. Alcolea PJ, Tuñón GI, Alonso A, García-Tabares F, et al. Differential protein abundance in promastigotes of nitric oxide-sensitive and resistant Leishmania chagasi strains. Proteomics Clin Appl. 2016;10:1132–46.

    Article  PubMed  CAS  Google Scholar 

  65. Yau WL, Lambertz U, Colineau L, Pescher P, et al. Phenotypic characterization of a Leishmania donovani cyclophilin 40 null mutant. J Eukaryot Microbiol. 2016;63:823–33.

    Article  PubMed  CAS  Google Scholar 

  66. Thiel M, Bruchhaus I. Comparative proteome analysis of Leishmania donovani at different stages of transformation from promastigotes to amastigotes. Med Microbiol Immunol. 2001;190:33–6.

    Article  PubMed  CAS  Google Scholar 

  67. El Fakhry Y, Ouellette M, Papadopoulou B. A proteomic approach to identify developmentally regulated proteins in Leishmania infantum. Proteomics. 2002;2:1007–17.

    Article  PubMed  Google Scholar 

  68. Bente M, Harder S, Wiesgigl M, Heukeshoven J, et al. Developmentally induced changes of the proteome in the protozoan parasite Leishmania donovani. Proteomics. 2003;3:1811–29.

    Article  PubMed  CAS  Google Scholar 

  69. Nugent PG, Karsani SA, Wait R, Tempero J, et al. Proteomic analysis of Leishmania mexicana differentiation. Mol Biochem Parasitol. 2004;136:51–62.

    Article  PubMed  CAS  Google Scholar 

  70. Walker J, Vasquez JJ, Gomez MA, Drummelsmith J, et al. Identification of developmentally-regulated proteins in Leishmania panamensis by proteome profiling of promastigotes and axenic amastigotes. Mol Biochem Parasitol. 2006;147:64–73.

    Article  PubMed  CAS  Google Scholar 

  71. Foucher AL, Papadopoulou B, Ouellette M. Prefractionation by digitonin extraction increases representation of the cytosolic and intracellular proteome of Leishmania infantum. J Proteome Res. 2006;5:1741–50.

    Article  PubMed  CAS  Google Scholar 

  72. Rosenzweig D, Smith D, Opperdoes F, Stern S, et al. Retooling Leishmania metabolism: from sand fly gut to human macrophage. FASEB J. 2008a;22:590–602.

    Article  PubMed  CAS  Google Scholar 

  73. Morales MA, Watanabe R, Laurent C, Lenormand P, et al. Phosphoproteomic analysis of Leishmania donovani pro- and amastigote stages. Proteomics. 2008;8:350–63.

    Article  PubMed  CAS  Google Scholar 

  74. Mojtahedi Z, Clos J, Kamali-Sarvestani E. Leishmania major: identification of developmentally regulated proteins in procyclic and metacyclic promastigotes. Exp Parasitol. 2008;119:422–9.

    Article  PubMed  CAS  Google Scholar 

  75. Paape D, Lippuner C, Schmid M, Ackermann R, et al. Transgenic, fluorescent Leishmania mexicana allow direct analysis of the proteome of intracellular amastigotes. Mol Cell Proteomics. 2008;7:1688–701.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Nirujogi RS, Pawar H, Renuse S, Kumar P, et al. Moving from unsequenced to sequenced genome: reanalysis of the proteome of Leishmania donovani. J Proteomics. 2014;97:48–61.

    Article  PubMed  CAS  Google Scholar 

  77. Rosenzweig D, Smith D, Myler PJ, Olafson RW, et al. Post-translational modification of cellular proteins during Leishmania donovani differentiation. Proteomics. 2008b;8:1843–50.

    Article  PubMed  CAS  Google Scholar 

  78. Hem S, Gherardini PF, Osorio y Fortéa J, Hourdel V, et al. Identification of Leishmania-specific protein phosphorylation sites by LC-ESI-MS/MS and comparative genomics analyses. Proteomics. 2010;10:3868–83.

    Article  PubMed  CAS  Google Scholar 

  79. Moreira D de S, Pescher P, Laurent C, Lenormand P, et al. Phosphoproteomic analysis of wild-type and antimony-resistant Leishmania braziliensis lines by 2D-DIGE technology. Proteomics. 2015;15:2999–3019.

    Article  CAS  Google Scholar 

  80. Bachmaier S, Witztum R, Tsigankov P, Koren R, et al. Protein kinase A signaling during bidirectional axenic differentiation in Leishmania. Int J Parasitol. 2016;46:75–82.

    Article  PubMed  CAS  Google Scholar 

  81. Morales MA, Watanabe R, Dacher M, Chafey P, et al. Phosphoproteome dynamics reveal heat-shock protein complexes specific to the Leishmania donovani infectious stage. Proc Natl Acad Sci USA. 2010;107:8381–6.

    Article  PubMed  PubMed Central  Google Scholar 

  82. de Oliveira AH, Ruiz JC, Cruz AK, Greene LJ, et al. Subproteomic analysis of soluble proteins of the microsomal fraction from two Leishmania species. Comp Biochem Physiol Part D Genomic Proteomics. 2006;1:300–8.

    Article  CAS  Google Scholar 

  83. Hide M, Ritleng AS, Brizard JP, Monte-Allegre A, et al. Leishmania infantum: tuning digitonin fractionation for comparative proteomic of the mitochondrial protein content. Parasitol Res. 2008;103:989–92.

    Article  PubMed  CAS  Google Scholar 

  84. Silverman JM, Chan SK, Robinson DP, Dwyer DM, et al. Proteomic analysis of the secretome of Leishmania donovani. Genome Biol. 2008;9:R35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Cuervo P, De Jesus JB, Saboia-Vahia L, Mendonça-Lima L, et al. Proteomic characterization of the released/secreted proteins of Leishmania (Viannia) braziliensis promastigotes. J Proteomics. 2009;73:79–92.

    Article  PubMed  CAS  Google Scholar 

  86. Brotherton MC, Racine G, Ouameur AA, Leprohon P, et al. Analysis of membrane-enriched and high molecular weight proteins in Leishmania infantum promastigotes and axenic amastigotes. J Proteome Res. 2012;11:3974–85.

    Article  PubMed  CAS  Google Scholar 

  87. Lynn MA, Marr AK, McMaster WR. Differential quantitative proteomic profiling of Leishmania infantum and Leishmania mexicana density gradient separated membranous fractions. J Proteomics. 2013;82:179–92.

    Article  PubMed  CAS  Google Scholar 

  88. Santarém N, Racine G, Silvestre R, Cordeiro-da-Silva A, et al. Exoproteome dynamics in Leishmania infantum. J Proteomics. 2013;84:106–18.

    Article  PubMed  CAS  Google Scholar 

  89. Atayde VD, Aslan H, Townsend S, Hassani K, et al. Exosome secretion by the parasitic protozoan Leishmania within the sand fly midgut. Cell Rep. 2015;13:957–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Kumar A, Misra P, Sisodia B, Shasany AK, et al. Proteomic analyses of membrane enriched proteins of Leishmania donovani Indian clinical isolate by mass spectrometry. Parasitol Int. 2015;64:36–42.

    Article  PubMed  CAS  Google Scholar 

  91. Lima BS, Fialho LC Jr, Pires SF, Tafuri WL, et al. Immunoproteomic and bioinformatic approaches to identify secreted Leishmania amazonensis, L. braziliensis, and L. infantum proteins with specific reactivity using canine serum. Vet Parasitol. 2016;223:115–9.

    Article  PubMed  CAS  Google Scholar 

  92. Drummelsmith J, Girard I, Trudel N, Ouellette M. Differential protein expression analysis of Leishmania major reveals novel roles for methionine adenosyltransferase and S-adenosylmethionine in methotrexate resistance. J Biol Chem. 2004;279:33273–80.

    Article  PubMed  CAS  Google Scholar 

  93. Vergnes B, Gourbal B, Girard I, Sundar S, et al. 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. 2007;6:88–101.

    Article  PubMed  CAS  Google Scholar 

  94. El Fadili K, Drummelsmith J, Roy G, Jardim A, et al. Down regulation of KMP-11 in Leishmania infantum axenic antimony resistant amastigotes as revealed by a proteomic screen. Exp Parasitol. 2009;123:51–7.

    Article  PubMed  CAS  Google Scholar 

  95. Matrangolo FS, Liarte DB, Andrade LC, de Melo MF, et al. Comparative proteomic analysis of antimony-resistant and -susceptible Leishmania braziliensis and Leishmania infantum chagasi lines. Mol Biochem Parasitol. 2013;190:63–75.

    Article  PubMed  CAS  Google Scholar 

  96. Carnielli JB, de Andrade HM, Pires SF, Chapeaurouge AD, et al. Proteomic analysis of the soluble proteomes of miltefosine-sensitive and -resistant Leishmania infantum chagasi isolates obtained from Brazilian patients with different treatment outcomes. J Proteomics. 2014;108:198–208.

    Article  PubMed  CAS  Google Scholar 

  97. Singh G, Chavan HD, Dey CS. Proteomic analysis of miltefosine-resistant Leishmania reveals the possible involvement of eukaryotic initiation factor 4A (eIF4A). Int J Antimicrob Agents. 2008a;31:584–6.

    Article  PubMed  CAS  Google Scholar 

  98. Singh G, Jayanarayan KG, Dey CS. Arsenite resistance in Leishmania and possible drug targets. Adv Exp Med Biol. 2008b;625:1–8.

    Article  PubMed  CAS  Google Scholar 

  99. Vincent IM, Racine G, Légaré D, Ouellette M. Mitochondrial proteomics of antimony and miltefosine resistant Leishmania infantum. Proteomes. 2015;3:328–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Akpunarlieva S, Weidt S, Lamasudin D, Naula C, et al. Integration of proteomics and metabolomics to elucidate metabolic adaptation in Leishmania. J Proteomics. 2017;155:85–98.

    Article  PubMed  CAS  Google Scholar 

  101. Sharma S, Singh G, Chavan HD, Dey CS. Proteomic analysis of wild type and arsenite-resistant Leishmania donovani. Exp Parasitol. 2009;123:369–76.

    Article  PubMed  CAS  Google Scholar 

  102. Kumar A, Sisodia B, Misra P, Sundar S, et al. Proteome mapping of overexpressed membrane-enriched and cytosolic proteins in sodium antimony gluconate (SAG) resistant clinical isolate of Leishmania donovani. Br J Clin Pharmacol. 2010;70:609–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Peláez RG, Muskus CE, Cuervo P, Marín-Villa M. Differential expression of proteins in Leishmania (Viannia) panamensis associated with mechanisms of resistance to meglumine antimoniate. Biomedica. 2012;32:418–29.

    Article  PubMed  Google Scholar 

  104. Walker J, Gongora R, Vasquez JJ, Drummelsmith J, et al. Discovery of factors linked to antimony resistance in Leishmania panamensis through differential proteome analysis. Mol Biochem Parasitol. 2012;183:166–76.

    Article  PubMed  CAS  Google Scholar 

  105. Messaritakis I, Christodoulou V, Mazeris A, Koutala E, et al. Drug resistance in natural isolates of Leishmania donovani s.l. promastigotes is dependent of Pgp170 expression. PLoS One. 2013;8:e65467.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Brotherton MC, Bourassa S, Leprohon P, Légaré D, et al. Proteomic and genomic analyses of antimony resistant Leishmania infantum mutant. PLoS One. 2013;8:e81899.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Brotherton MC, Bourassa S, Légaré D, Poirier GG, et al. Quantitative proteomic analysis of amphotericin B resistance in Leishmania infantum. Int J Parasitol Drugs Drug Resist. 2014;4:126–32.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Vacchina P, Norris-Mullins B, Carlson ES, Morales MA. A mitochondrial HSP70 (HSPA9B) is linked to miltefosine resistance and stress response in Leishmania donovani. Parasit Vectors. 2016;9:621.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. MacGillivray AJ, Rickwood D. The heterogeneity of mouse-chromatin nonhistone proteins as evidenced by two-dimensional polyacrylamide-gel electrophoresis and ion-exchange chromatography. Eur J Biochem. 1974;41:181–90.

    Article  PubMed  CAS  Google Scholar 

  110. O’Farrell PH. High resolution two-dimensional electrophoresis of proteins. J Biol Chem. 1975;250:4007–21.

    PubMed  Google Scholar 

  111. Anderson L, Anderson NG. High resolution two-dimensional electrophoresis of human plasma proteins. Proc Natl Acad Sci USA. 1977;74:5421–5.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  112. Bravo R, Celis JE. A search for differential polypeptide synthesis throughout the cell cycle of HeLa cells. J Cell Biol. 1980;84:795–802.

    Article  PubMed  CAS  Google Scholar 

  113. Taylor J, Anderson NL, Scandora AE Jr, Willard KE, et al. Design and implementation of a prototype human protein index. Clin Chem. 1982;28:861–6.

    PubMed  CAS  Google Scholar 

  114. Handman E, Mitchell GF, Goding JW. Identification and characterization of protein antigens of Leishmania tropica isolates. J Immunol. 1981;126:508–12.

    PubMed  CAS  Google Scholar 

  115. Saravia NG, Gemmell MA, Nance SL, Anderson NL. Two-dimensional electrophoresis used to differentiate the causal agents of American tegumentary leishmaniasis. Clin Chem. 1984;30:2048–52.

    PubMed  CAS  Google Scholar 

  116. Fong D, Chang KP. Tubulin biosynthesis in the developmental cycle of a parasitic protozoan, Leishmania mexicana: changes during differentiation of motile and nonmotile stages. Proc Natl Acad Sci USA. 1981;78:7624–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Arrebola R, Olmo A, Reche P, Garvey EP, et al. Isolation and characterization of a mutant dihydrofolate reductase-thymidylate synthase from methotrexate-resistant Leishmania cells. J Biol Chem. 1994;269:10590–6.

    PubMed  CAS  Google Scholar 

  118. Görg A, Postel W, Günther S. The current state of two-dimensional electrophoresis with immobilized pH gradients. Electrophoresis. 1988;9:531–46.

    Article  PubMed  Google Scholar 

  119. Matsudaira PT. Sequence from picomole quantities of proteins electroblotted onto polyvinylidene difluoride membranes. J Biol Chem. 1987;262:10035–8.

    PubMed  CAS  Google Scholar 

  120. Carrette O, Burkhard PR, Sanchez JC, Hochstrasser DF. State-of-the-art two-dimensional gel electrophoresis: a key tool of proteomics research. Nat Protoc. 2006;1:812–23.

    Article  PubMed  CAS  Google Scholar 

  121. Rabilloud T, Chevallet M, Luche S, Lelong C. Two-dimensional gel electrophoresis in proteomics: past, present and future. J Proteomics. 2010;73:2064–77.

    Article  PubMed  CAS  Google Scholar 

  122. Bantscheff M, Lemeer S, Savitski MM, Kuster B. Quantitative mass spectrometry in proteomics: critical review update from 2007 to the present. Anal Bioanal Chem. 2012;404:939–65.

    Article  PubMed  CAS  Google Scholar 

  123. Duncan MW, Aebersold R, Caprioli RM. The pros and cons of peptide-centric proteomics. Nat Biotechnol. 2010;28:659–64.

    Article  PubMed  CAS  Google Scholar 

  124. Biyani N, Singh AK, Mandal S, Chawla B. Differential expression of proteins in antimony-susceptible and -resistant isolates of Leishmania donovani. Mol Biochem Parasitol. 2011;179:91–9.

    Article  PubMed  CAS  Google Scholar 

  125. Altelaar AF, Munoz J, Heck AJ. Next-generation proteomics: towards an integrative view of proteome dynamics. Nat Rev Genet. 2013;14:35–48.

    Article  PubMed  CAS  Google Scholar 

  126. Wiśniewski JR, Hein M, Cox J, Mann M. A “Proteomic Ruler” for protein copy number and concentration estimation without spike-in standards. Mol Cell Proteomics. 2014;13:3497–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Reddy PJ, Jain R, Paik YK, Downey R, et al. Personalized medicine in the age of pharmacoproteomics: a close up on India and need for social science engagement for responsible innovation in post-proteomic biology. Curr Pharmacogenomics Person Med. 2011;9:67–75.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Matthews H, Hanison J, Nirmalan N. “Omics”-informed drug and biomarker discovery: opportunities, challenges and future perspectives. Proteomes. 2016;4:E28.

    Article  PubMed  Google Scholar 

  129. Goldstein RL, Yang SN, Taldone T, Chang B, et al. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J Clin Invest. 2015;125:4559–71.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Shu S, Lin CY, He HH, Witwicki RM, et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature. 2016;529:413–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Detke S, Katakura K, Chang KP. DNA amplification in arsenite resistant Leishmania. Exp Cell Res. 1989;180:161–70.

    Article  PubMed  CAS  Google Scholar 

  132. Ouellette M, Hettema E, Wust D, Fase-Fowler F, et al. Direct and inverted DNA repeats associated with P-glycoprotein gene amplification in drug resistant Leishmania. EMBO J. 1991;10:1009–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Callahan HL, Beverley SM. Heavy metal resistance: A new role for P-glycoproteins in Leishmania. J Biol Chem. 1991;266:18427–30.

    PubMed  CAS  Google Scholar 

  134. Bello AR, Nare B, Freedman D, Hardy L, et al. PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc Natl Acad Sci USA. 1994;91:11442–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  135. Prasad V, Kaur J, Dey CS. Arsenite-resistant Leishmania donovani promastigotes express an enhanced membrane P-type adenosine triphosphatase activity that is sensitive to verapamil treatment. Parasitol Res. 2000;86:661–4.

    Article  PubMed  CAS  Google Scholar 

  136. Richard D, Kündig C, Ouellette M. A new type of high affinity folic acid transporter in the protozoan parasite Leishmania and deletion of its gene in methotrexate-resistant cells. J Biol Chem. 2002;277:29460–7.

    Article  PubMed  CAS  Google Scholar 

  137. HaimeurA GC, Pilote S, Mukhopadhyay R, Rosen BP, et al. Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite-resistant Leishmania. Mol Microbiol. 1999;34:726–35.

    Article  Google Scholar 

  138. Brochu C, Wang J, Roy G, Messier N, et al. Antimony uptake systems in the protozoan parasite Leishmania and accumulation differences in antimony-resistant parasites. Antimicrob Agents Chemother. 2003;47:3073–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Ouellette M, Drummelsmith J, Papadopoulou B. Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist Updat. 2004;7:257–66.

    Article  PubMed  CAS  Google Scholar 

  140. Ashutosh SS, Goyal N. Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol. 2007;56:143–53.

    Article  PubMed  CAS  Google Scholar 

  141. Ouellette M, Borst P. Drug resistance and P-glycoprotein gene amplification in the protozoan parasite Leishmania. Res Microbiol. 1991;142:737–46.

    Article  PubMed  CAS  Google Scholar 

  142. Beverley SM. Gene amplification in Leishmania. Annu Rev Microbiol. 1991;45:417–44.

    Article  PubMed  CAS  Google Scholar 

  143. Dey S, Papadopoulou B, Haimeur A, Roy G, et al. High level arsenite resistance in Leishmania tarentolae is mediated by an active extrusion system. Mol Biochem Parasitol. 1994;67:49–57.

    Article  PubMed  CAS  Google Scholar 

  144. Dey S, Ouellette M, Lightbody J, Papadopoulou B, Rosen BP. An ATP-dependent As(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. Proc Natl Acad Sci USA. 1996;93:2192–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  145. Mukhopadhyay R, Dey S, Xu N, Gage D, et al. Trypanothione overproduction and resistance to antimonials and arsenicals in Leishmania. Proc Natl Acad Sci USA. 1996;93:10383–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  146. Coderre JA, Beverley SM, Schimke RT, Santi DV. Overproduction of a bifunctional thymidylate synthetase-dihydrofolate reductase and DNA amplification in methotrexate-resistant Leishmania tropica. Proc Natl Acad Sci USA. 1983;80:2132–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  147. Croft SL, Coombs GH. Leishmaniasis—current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol. 2003;19:502–8.

    Article  PubMed  CAS  Google Scholar 

  148. Thakur CP, Sinha GP, Pandey AK, Kumar N, et al. Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases. Ann Trop Med Parasitol. 1998;92:561–9.

    Article  PubMed  CAS  Google Scholar 

  149. Sundar S, More DK, Singh MK, Singh VP, et al. Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic. Clin Infect Dis. 2000;31:1104–1107s.

    Article  PubMed  CAS  Google Scholar 

  150. Perry MR, Wyllie S, Prajapati VK, Feldmann J, et al. Visceral leishmaniasis and arsenic: an ancient poison contributing to antimonial treatment failure in the Indian subcontinent? PLoS Negl Trop Dis. 2011;5:e1227.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Berman JD, Chulay JD, Hendricks LD, Oster CN. Susceptibility of clinically sensitive and resistant Leishmania to pentavalent antimony in vitro. Am J Trop Med Hyg. 1982;31:459–65.

    Article  PubMed  CAS  Google Scholar 

  152. Navin TR, Arana BA, Arana FE, Berman JD, et al. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis. 1992;165:528–34.

    Article  PubMed  CAS  Google Scholar 

  153. Burguera J, Burguera M, Petit de Pena Y, Lugo A, et al. Selective determination of antimony(III) and antimony(V) in serum and urine and of total antimony in skin biopsies of patients with cutaneous leishmaniasis treated with meglumine antimoniate. Trace Elem Med. 1993;10:66–70.

    Google Scholar 

  154. Callahan HL, Portal AC, Devereaux R, Grogl M. An axenic amastigote system for drug screening. Antimicrob Agents Chemother. 1997;41:818–22.

    PubMed  PubMed Central  CAS  Google Scholar 

  155. Ephros M, Bitnun A, Shaked P, Waldman E, Zilberstein D. Stage-specific activity of pentavalent antimony against Leishmania donovani axenic amastigotes. Antimicrob Agents Chemother. 1999;43:278–82.

    PubMed  PubMed Central  CAS  Google Scholar 

  156. Shaked-Mishan P, Ulrich N, Ephros M, Zilberstein D. Novel intracellular SbV reducing activity correlates with antimony susceptibility in Leishmania donovani. J Biol Chem. 2001;276:3971–6.

    Article  PubMed  CAS  Google Scholar 

  157. Denton H, McGregor JC, Coombs GH. Reduction of anti-leishmanial pentavalent antimonial drugs by a parasite-specific thiol-dependent reductase, TDR1. Biochem J. 2004;381:405–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Zhou Y, Messier N, Ouellette M, Rosen BP, et al. Leishmania major LmACR2 is a pentavalent antimony reductase that confers sensitivity to the drug pentostam. J Biol Chem. 2004;279:37445–51.

    Article  PubMed  CAS  Google Scholar 

  159. Mukhopadhyay R, Bisacchi D, Zhou Y, Armirotti A, et al. Structural characterization of the As/Sb reductase LmACR2 from Leishmania major. J Mol Biol. 2009;386:1229–39.

    Article  PubMed  CAS  Google Scholar 

  160. Frézard F, Demicheli C, Ferreira CS, Costa MA. Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate. Antimicrob Agents Chemother. 2001;45:913–6.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Tsukaguchi H, Shayakul C, Berger UV, Mackenzie B, et al. Molecular characterization of a broad selectivity neutral solute channel. J Biol Chem. 1998;273:24737–43.

    Article  PubMed  CAS  Google Scholar 

  162. Gourbal B, Sonuc N, Bhattacharjee H, Legare D, et al. Drug uptake and modulation of drug resistance in Leishmania by an aquaglyceroporin. J Biol Chem. 2004;279:31010–7.

    Article  PubMed  CAS  Google Scholar 

  163. Decuypere S, Rijal S, Yardley V, De Doncker S, et al. Gene expression analysis of the mechanism of natural Sb(V) resistance in Leishmania donovani isolates from Nepal. Antimicrob Agents Chemother. 2005;49:4616–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Marquis N, Gourbal B, Rosen BP, Mukhopadhyay R. Modulation in aquaglyceroporin AQP1 gene transcript levels in drug-resistant Leishmania. Mol Microbiol. 2005;57:1690–9.

    Article  PubMed  CAS  Google Scholar 

  165. Wyllie S, Cunningham ML, Fairlamb AH. Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. J Biol Chem. 2004;279:39925–32.

    Article  PubMed  CAS  Google Scholar 

  166. Berman JD, Waddell D, Hanson BD. Biochemical mechanisms of the antileishmanial activity of sodium stibogluconate. Antimicrob Agents Chemother. 1985;27:916–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Sereno D, Holzmuller P, Mangot I, Cuny G. Antimonial-mediated DNA fragmentation in Leishmania infantum amastigotes. Antimicrob Agents Chemother. 2001;45:2064–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Sudhandiran G, Shaha C. Antimonial-induced increase in intracellular Ca2+ through non-selective cation channels in the host and the parasite is responsible for apoptosis of intracellular Leishmania donovani amastigotes. J Biol Chem. 2003;278:25120–32.

    Article  PubMed  CAS  Google Scholar 

  169. Grondin K, Haimeur A, Mukhopadhyay R, Rosen BP, et al. Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J. 1997;16:3057–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Haimeur A, Brochu C, Genest P, Papadopoulou B, et al. Amplification of the ABC transporter gene PGPA and increased trypanothione levels in potassium antimonyl tartrate (SbIII) resistant Leishmania tarentolae. Mol Biochem Parasitol. 2000;108:131–5.

    Article  PubMed  CAS  Google Scholar 

  171. Callahan HL, Roberts WL, Rainey PM, Beverley SM. The PGPA gene of Leishmania major mediates antimony (SbIII) resistance by decreasing influx and not by increasing efflux. Mol Biochem Parasitol. 1994;68:145–9.

    Article  PubMed  CAS  Google Scholar 

  172. Légaré D, Richard D, Mukhopadhyay R, Stierhof YD, et al. The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J Biol Chem. 2001;276:26301–7.

    Article  PubMed  Google Scholar 

  173. Mittal MK, Rai S, Ravinder GS, Sundar S, et al. Characterization of natural antimony resistance in Leishmania donovani isolates. Am J Trop Med Hyg. 2007;76:681–8.

    Article  PubMed  CAS  Google Scholar 

  174. Goyeneche-Patino DA, Valderrama L, Walker J, Saravia NG. Antimony resistance and trypanothione in experimentally selected and clinical strains of Leishmania panamensis. Antimicrob Agents Chemother. 2008;52:4503–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Mukherjee A, Padmanabhan PK, Singh S, Roy G, et al. Role of ABC transporter MRPA, gamma-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. J Antimicrob Chemother. 2007;59:204–11.

    Article  PubMed  CAS  Google Scholar 

  176. Mandal G, Sarkar A, Saha P, Singh N, et al. Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates. Indian J Biochem Biophys. 2009;46:86–92.

    PubMed  CAS  Google Scholar 

  177. Monte-Neto R, Laffitte MC, Leprohon P, Reis P, et al. Intrachromosomal amplification, locus deletion and point mutation in the aquaglyceroporin AQP1 gene in antimony resistant Leishmania (Viannia) guyanensis. PLoS Negl Trop Dis. 2015;9:e0003476.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Hefnawy A, Berg M, Dujardin JC, De Muylder G. Exploiting knowledge on Leishmania drug resistance to support the quest for new drugs. Trends Parasitol. 2017;33:162–74.

    Article  PubMed  CAS  Google Scholar 

  179. Jardim A, Hanson S, Ullman B, McCubbin WD, et al. Cloning and structure-function analysis of the Leishmania donovani kinetoplastid membrane protein-11. Biochem J. 1995;305:315–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Fuertes MA, Berberich C, Lozano RM, Gimenez-Gallego G, et al. Folding stability of the kinetoplastid membrane protein-11 (KMP-11) from Leishmania infantum. Eur J Biochem. 1999;260:559–67.

    Article  PubMed  CAS  Google Scholar 

  181. Lee N, Bertholet S, Debrabant A, Muller J, et al. Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death Differ. 2002;9:53–64.

    Article  PubMed  CAS  Google Scholar 

  182. Cohen-Saidon C, Carmi I, Keren A, Razin E. Antiapoptotic function of Bcl-2 in mast cells is dependent on its association with heat shock protein 90. Blood. 2006;107:1413–20.

    Article  PubMed  CAS  Google Scholar 

  183. Das S, Shah P, Tandon R, Yadav NK, et al. Over-expression of cysteine leucine rich protein is related to SAG resistance in clinical isolates of Leishmania donovani. PLoS Negl Trop Dis. 2015;9:e0003992.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Das S, Shah P, Baharia RK, Tandon R, et al. Over-expression of 60s ribosomal L23a is associated with cellular proliferation in SAG resistant clinical isolates of Leishmania donovani. PLoS Negl Trop Dis. 2013;7:e2527.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Dridi L, Ahmed Ouameur A, Ouellette M. High affinity S-Adenosylmethionine plasma membrane transporter of Leishmania is a member of the folate biopterin transporter (FBT) family. J Biol Chem. 2010;285:19767–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Vickers TJ, Beverley SM. Folate metabolic pathways in Leishmania. Essays Biochem. 2011;51:63–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Wiśniewski JR, Zougman A, Mann M. Combination of FASP and StageTip-based fractionation allows in-depth analysis of the hippocampal membrane proteome. J Proteome Res. 2009a;8:5674–8.

    Article  PubMed  CAS  Google Scholar 

  188. Wiśniewski JR, Duś-Szachniewicz K, Ostasiewicz P, Ziółkowski P, et al. Absolute proteome analysis of colorectal mucosa, adenoma, and cancer reveals drastic changes in fatty acid metabolism and plasma membrane transporters. J Proteome Res. 2015;14:4005–18.

    Article  PubMed  CAS  Google Scholar 

  189. Vildhede A, Wiśniewski JR, Norén A, Karlgren M, et al. Comparative proteomic analysis of human liver tissue and isolated hepatocytes with a focus on proteins determining drug exposure. J Proteome Res. 2015;14:3305–14.

    Article  PubMed  CAS  Google Scholar 

  190. Tandon R, Chandra S, Baharia RK, Das S, et al. Characterization of the proliferating cell nuclear antigen of Leishmania donovani clinical isolates and its association with antimony resistance. Antimicrob Agents Chemother. 2014;58:2997–3007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Parodi-Talice A, Durán R, Arrambide N, Prieto V, et al. Proteome analysis of the causative agent of Chagas disease: Trypanosoma cruzi. Int J Parasitol. 2004;34:881–6.

    Article  PubMed  CAS  Google Scholar 

  192. Croft SL, Neal RA, Pendergast W, Chan JH. The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani. Biochem Pharmacol. 1987;36:2633–6.

    Article  PubMed  CAS  Google Scholar 

  193. Kuhlencord A, Maniera T, Eibl H, Unger C. Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice. Antimicrob Agents Chemother. 1992;36:1630–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Sundar S, Jha TK, Thakur CP, Engel J, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med. 2002;347:1739–46.

    Article  PubMed  CAS  Google Scholar 

  195. Soto J, Soto P. Miltefosine: oral treatment of leishmaniasis. Expert Rev Anti Infect Ther. 2006;4:177–85.

    Article  PubMed  CAS  Google Scholar 

  196. Sundar S, Mondal D, Rijal S, Bhattacharya S, et al. Implementation research to support the initiative on the elimination of kala azar from Bangladesh, India and Nepal–the challenges for diagnosis and treatment. Trop Med Int Health. 2008;13:2–5.

    Article  PubMed  Google Scholar 

  197. World Health Organization. Regional strategic framework for elimination of Kala-azar from the South-East Asia region (2005–2015). New Delhi: WHO Regional Office for South-East Asia; 2005.

    Google Scholar 

  198. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet. 2005;366:1561–77.

    Article  PubMed  CAS  Google Scholar 

  199. Calvopina M, Gomez EA, Sindermann H, Cooper PJ, et al. Relapse of new world diffuse cutaneous leishmaniasis caused by Leishmania (Leishmania) mexicana after miltefosine treatment. Am J Trop Med Hyg. 2006;75:1074–7.

    Article  PubMed  Google Scholar 

  200. Zerpa O, Ulrich M, Blanco B, Polegre M, et al. Diffuse cutaneous leishmaniasis responds to miltefosine but then relapses. Br J Dermatol. 2007;156:1328–35.

    Article  PubMed  CAS  Google Scholar 

  201. Pandey BD, Pandey K, Kaneko O, Yanagi T, et al. Relapse of visceral leishmaniasis after miltefosine treatment in a Nepalese patient. Am J Trop Med Hyg. 2009;80:580–2.

    Article  PubMed  Google Scholar 

  202. Andrade HM, Toledo VP, Pinheiro MB, Guimarães TM, et al. Evaluation of miltefosine for the treatment of dogs naturally infected with L. infantum (= L. chagasi) in Brazil. Vet Parasitol. 2011;181:83–90.

    Article  PubMed  CAS  Google Scholar 

  203. Proverbio D, Spada E, Bagnagatti De Giorgi G, Perego R. Failure of miltefosine treatment in two dogs with natural Leishmania infantum infection. Case Rep Vet Med. 2014;640151. https://doi.org/10.1155/2014/640151

  204. Escobar P, Matu S, Marques C, Croft SL. Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Trop. 2002;81:151–7.

    Article  PubMed  CAS  Google Scholar 

  205. van Blitterswijk WJ, Verheij M. Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des. 2008;14:2061–74.

    Article  PubMed  Google Scholar 

  206. Paris C, Loiseau PM, Bories C, Bréard J. Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrob Agents Chemother. 2004;48:852–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Croft SL, Seifert K, Duchêne M. Antiprotozoal activities of phospholipid analogues. Mol Biochem Parasitol. 2003;126:165–72.

    Article  PubMed  CAS  Google Scholar 

  208. Rakotomanga M, Blanc S, Gaudin K, Chaminade P, et al. Miltefosine affects lipid metabolism in Leishmania donovani promastigotes. Antimicrob Agents Chemother. 2007;51:1425–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Pérez-Victoria FJ, Sánchez-Cañete MP, Castanys S, Gamarro F. Phospholipid translocation and miltefosine potency require both L. donovani miltefosine transporter and the new protein LdRos3 in Leishmania parasites. J Biol Chem. 2006a;281:23766–75.

    Article  PubMed  CAS  Google Scholar 

  210. Sánchez-Cañete MP, Carvalho L, Pérez-Victoria FJ, Gamarro F, et al. Low plasma membrane expression of the miltefosine transport complex renders Leishmania braziliensis refractory to the drug. Antimicrob Agents Chemother. 2009;53:1305–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Pérez-Victoria FJ, Sánchez-Cañete MP, Seifert K, Croft SL, et al. Mechanisms of experimental resistance of Leishmania to miltefosine: Implications for clinical use. Drug Resist Updat. 2006b;9:26–39.

    Article  PubMed  CAS  Google Scholar 

  212. Montero-Lomelí M, Morais BL, Figueiredo DL, Neto DC, et al. The initiation factor eIF4A is involved in the response to lithium stress in Saccharomyces cerevisiae. J Biol Chem. 2002;277:21542–8.

    Article  PubMed  CAS  Google Scholar 

  213. Wiśniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods. 2009b;6:359–62.

    Article  PubMed  CAS  Google Scholar 

  214. Priotto G, Kasparian S, Mutombo W, Ngouama D, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009;374:56–64.

    Article  PubMed  CAS  Google Scholar 

  215. Gygi SP, Corthals GL, Zhang Y, Rochon Y, et al. Evaluation of two-dimensional gel electrophoresis-based proteome analysis technology. Proc Natl Acad Sci USA. 2000;97:9390–5.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  216. Junqueira M, Spirin V, Santana Balbuena T, Waridel P, et al. Separating the wheat from the chaff: unbiased filtering of background tandem mass spectra improves protein identification. J Proteome Res. 2008;7:3382–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Lye LF, Owens K, Shi H, Murta SM, et al. Retention and loss of RNA interference pathways in trypanosomatid protozoans. PLoS Pathog. 2010;6:e1001161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Carter KC, Hutchison S, Henriquez FL, Légaré D, et al. Resistance of Leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase. Antimicrob Agents Chemother. 2006;50:88–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Araujo RP, Liotta LA, Petricoin EF. Proteins, drug targets and the mechanisms they control: the simple truth about complex networks. Nat Rev Drug Discov. 2007;6:871–80.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Patricia Cuervo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Saboia-Vahia, L., de Jesus, J.B., Cuervo, P. (2018). The Role of Proteomics in the Study of Drug Resistance. In: Ponte-Sucre, A., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Cham. https://doi.org/10.1007/978-3-319-74186-4_10

Download citation

Publish with us

Policies and ethics