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Genetic Expression and Drug Resistance, the Role of Proteomics

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Drug Resistance in Leishmania Parasites

Summary

The recent completion of the genomic sequencing of three species of Leishmania, L. major, L. infantum, and L. 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.

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References

  • Abdo MG et al (2003) Antimony-resistant Leishmania donovani in eastern Sudan: incidence and in vitro correlation. East Mediterr Health J 9:837–843

    PubMed  CAS  Google Scholar 

  • Acestor N et al (2002) Establishing two-dimensional gels for the analysis of Leishmania proteomes. Proteomics 2:877–879

    PubMed  CAS  Google Scholar 

  • Akopyants NS et al (2004) 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 136:71–86

    PubMed  CAS  Google Scholar 

  • Almeida R et al (2004) Expression profiling of the Leishmania life cycle: cDNA arrays identify developmentally regulated genes present but not annotated in the genome. Mol Biochem Parasitol 136:87–100

    PubMed  CAS  Google Scholar 

  • Anderson L, Anderson NG (1977) High resolution two-dimensional electrophoresis of human plasma proteins. Proc Natl Acad Sci USA 74:5421–5425

    PubMed  CAS  Google Scholar 

  • Araujo RP, Liotta LA, Petricoin EF (2007) Proteins, drug targets and the mechanisms they control: the simple truth about complex networks. Nat Rev Drug Discov 6:871–880

    PubMed  CAS  Google Scholar 

  • Arrebola R et al (1994) Isolation and characterization of a mutant dihydrofolate reductase-thymidylate synthase from methotrexate-resistant Leishmania cells. J Biol Chem 269:10590–10596

    PubMed  CAS  Google Scholar 

  • Ashutosh, Sundar S, Goyal N (2007) Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 56:143–153

    PubMed  CAS  Google Scholar 

  • Bello AR et al (1994) PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc Natl Acad Sci USA 91:11442–11446

    PubMed  CAS  Google Scholar 

  • Bente M et al (2003) Developmentally induced changes of the proteome in the protozoan parasite Leishmania donovani. Proteomics 3:1811–1829

    PubMed  CAS  Google Scholar 

  • Berman JD et al (1982) Susceptibility of clinically sensitive and resistant Leishmania to pentavalent antimony in vitro. Am J Trop Med Hyg 31:459–465

    PubMed  CAS  Google Scholar 

  • Berman JD, Waddell D, Hanson BD (1985) Biochemical mechanisms of the antileishmanial activity of sodium stibogluconate. Antimicrob Agents Chemother 27:916–920

    PubMed  CAS  Google Scholar 

  • Beverley SM (1991) Gene amplification in Leishmania. Annu Rev Microbiol 45:417–444

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Brobey RK, Soong L (2007) Establishing a liquid-phase IEF in combination with 2-DE for the analysis of Leishmania proteins. Proteomics 7:116–120

    PubMed  CAS  Google Scholar 

  • Brobey RK et al (2006) Comparative two-dimensional gel electrophoresis maps for promastigotes of Leishmania amazonensis and Leishmania major. Braz J Infect Dis 10:1–6

    PubMed  Google Scholar 

  • Brochu C et al (2003) Antimony uptake systems in the protozoan parasite Leishmania and accumulation differences in antimony-resistant parasites. Antimicrob Agents Chemother 47:3073–3079

    PubMed  CAS  Google Scholar 

  • Burguera J et al (1993) 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 10:66–70

    Google Scholar 

  • Callahan HL, Beverley SM (1991) Heavy metal resistance: a new role for P-glycoproteins in Leishmania. J Biol Chem 266:18427–18430

    PubMed  CAS  Google Scholar 

  • Callahan HL et al (1994) The PGPA gene of Leishmania major mediates antimony (SbIII) resistance by decreasing influx and not by increasing efflux. Mol Biochem Parasitol 68:145–149

    PubMed  CAS  Google Scholar 

  • Callahan HL et al (1997) An axenic amastigote system for drug screening. Antimicrob Agents Chemother 41:818–822

    PubMed  CAS  Google Scholar 

  • Calvopina M et al (2006) Relapse of new world diffuse cutaneous leishmaniasis caused by Leishmania (Leishmania) mexicana after Miltefosine treatment. Am J Trop Med Hyg 75:1074–1077

    PubMed  Google Scholar 

  • Carrette O et al (2006) State-of-the-art two-dimensional gel electrophoresis: a key tool of proteomics research. Nat Protoc 1:812–823

    PubMed  CAS  Google Scholar 

  • Carter KC et al (2006) Resistance of Leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase. Antimicrob Agents Chemother 50:88–95

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Coderre JA et al (1983) Overproduction of a bifunctional thymidylate synthetase-dihydrofolate reductase and DNA amplification in methotrexate-resistant Leishmania tropica. Proc Natl Acad Sci USA 80:2132–2136

    PubMed  CAS  Google Scholar 

  • Cohen-Freue G et al (2007) Global gene expression in Leishmania. Int J Parasitol 37:1077–1086

    PubMed  CAS  Google Scholar 

  • Cohen-Saidon C et al (2006) Antiapoptotic function of Bcl-2 in mast cells is dependent on its association with heat shock protein 90. Blood 107:1413–1420

    PubMed  CAS  Google Scholar 

  • Croft SL, Coombs GH (2003) Leishmaniasis–current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol 19:502–508

    PubMed  CAS  Google Scholar 

  • Croft SL et al (1987) The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani. Biochem Pharmacol 36:2633–2636

    PubMed  CAS  Google Scholar 

  • Croft SL, Seifert K, Duchêne M (2003) Antiprotozoal activities of phospholipid analogues. Mol Biochem Parasitol 126:165–172

    PubMed  CAS  Google Scholar 

  • Croft SL, Sundar S, Fairlamb AH (2006) Drug resistance in Leishmaniasis. Clin Microbiol Rev 19:111–126

    PubMed  CAS  Google Scholar 

  • Cuervo P et al (2007) Proteome analysis of Leishmania (Viannia) braziliensis by two-dimensional gel electrophoresis and mass spectrometry. Mol Biochem Parasitol 154:6–21

    PubMed  CAS  Google Scholar 

  • Cuervo P et al (2009) Proteomic characterization of the released/secreted proteins of Leishmania (Viannia) braziliensis promastigotes. J Proteomics 73:79–92

    PubMed  CAS  Google Scholar 

  • Cuervo P, Domont GB, De Jesus JB (2010) Proteomics of trypanosomatids of human medical importance. J Proteomics 73:845–867

    PubMed  CAS  Google Scholar 

  • Das VN et al (2005) Magnitude of unresponsiveness to sodium stibogluconate in the treatment of visceral Leishmaniasis in Bihar. Natl Med J India 18:131–133

    PubMed  CAS  Google Scholar 

  • de Saldanha da Gama J et al (2011) Chemo-resistant protein expression pattern of glioblastoma cells (A172) to perillyl alcohol. J Proteome Res 10:153–160

    Google Scholar 

  • de Oliveira AH et al (2006) Subproteomic analysis of soluble proteins of the microsomal fraction from two Leishmania species. Comp Biochem Physiol D Genomics Proteomics 1:300–308

    Google Scholar 

  • Decuypere S et al (2005) Gene expression analysis of the mechanism of natural SbV resistance in Leishmania donovani isolates from Nepal. Antimicrob Agents Chemother 49:4616–4621

    PubMed  CAS  Google Scholar 

  • Denton H, McGregor JC, Coombs GH (2004) Reduction of anti-leishmanial pentavalent antimonial drugs by a parasite-specific thiol-dependent reductase, TDR1. Biochem J 381:405–412

    PubMed  CAS  Google Scholar 

  • Depledge DP et al (2009) Comparative expression profiling of Leishmania: modulation in gene expression between species and in different host genetic backgrounds. PLoS Negl Trop Dis 3:e476

    PubMed  Google Scholar 

  • Detke S, Katakura K, Chang KP (1989) DNA amplification in arsenite resistant Leishmania. Exp Cell Res 180:161–170

    PubMed  CAS  Google Scholar 

  • Dey S et al (1994) High level arsenite resistance in Leishmania tarentolae is mediated by an active extrusion system. Mol Biochem Parasitol 67:49–57

    PubMed  CAS  Google Scholar 

  • Dey S et al (1996) An ATP-dependent As(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. Proc Natl Acad Sci USA 93:2192–2197

    PubMed  CAS  Google Scholar 

  • Drummelsmith J et al (2003) Proteome mapping of the protozoan parasite Leishmania and application to the study of drug targets and resistance mechanisms. Mol Cell Proteomics 2:146–155

    PubMed  CAS  Google Scholar 

  • Drummelsmith J et al (2004) Differential protein expression analysis of Leishmania major reveals novel roles for methionine adenosyltransferase and S-adenosylmethionine in methotrexate resistance. J Biol Chem 279:33273–33280

    PubMed  CAS  Google Scholar 

  • El Fadili K et al (2009) Down regulation of KMP-11 in Leishmania infantum axenic antimony resistant amastigotes as revealed by a proteomic screen. Exp Parasitol 123:51–57

    PubMed  CAS  Google Scholar 

  • El Fakhry Y, Ouellette M, Papadopoulou B (2002) A proteomic approach to identify developmentally regulated proteins in Leishmania infantum. Proteomics 2:1007–1017

    PubMed  CAS  Google Scholar 

  • El-Sayed NM et al (2005) Comparative genomics of trypanosomatid parasitic protozoa. Science 309:404–409

    PubMed  CAS  Google Scholar 

  • Ephros M et al (1999) Stage-specific activity of pentavalent antimony against Leishmania donovani axenic amastigotes. Antimicrob Agents Chemother 43:278–282

    PubMed  CAS  Google Scholar 

  • Escobar P et al (2002) Sensitivities of Leishmania species to hexadecylphosphocholine (Miltefosine), ET-18-OCH(3) (edelfosine) and Amphotericin-B. Acta Trop 81:151–157

    PubMed  CAS  Google Scholar 

  • Faraut-Gambarelli F et al (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 41:827–830

    PubMed  CAS  Google Scholar 

  • Fenn J et al (1989) Electrospray ionization for mass spectrometry of large biomolecules. Science 246:64–71

    PubMed  CAS  Google Scholar 

  • Florens L et al (2002) A proteomic view of the Plasmodium falciparum life cycle. Nature 419:520–526

    PubMed  CAS  Google Scholar 

  • Fong D, Chang KP (1981) 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 78:7624–7628

    PubMed  CAS  Google Scholar 

  • Foucher AL, Papadopoulou B, Ouellette M (2006) Prefractionation by digitonin extraction increases representation of the cytosolic and intracellular proteome of Leishmania infantum. J Proteome Res 5:1741–1750

    PubMed  CAS  Google Scholar 

  • Frézard F et al (2001) Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate. Antimicrob Agents Chemother 45:913–916

    PubMed  Google Scholar 

  • Fuertes MA et al (1999) Folding stability of the kinetoplastid membrane protein-11 (KMP-11) from Leishmania infantum. Eur J Biochem 260:559–567

    PubMed  CAS  Google Scholar 

  • Góngora R et al (2003) Mapping the proteome of Leishmania Viannia parasites using two-dimensional polyacrylamide gel electrophoresis and associated technologies. Biomedica 23:153–160

    PubMed  Google Scholar 

  • Görg A, Postel W, Günther S (1988) The current state of two-dimensional electrophoresis with immobilized pH gradients. Electrophoresis 9:531–546

    PubMed  Google Scholar 

  • Gourbal B et al (2004) Drug uptake and modulation of drug resistance in Leishmania by an aquaglyceroporin. J Biol Chem 279:31010–31017

    PubMed  CAS  Google Scholar 

  • Goyeneche-Patino DA et al (2008) Antimony resistance and trypanothione in experimentally selected and clinical strains of Leishmania panamensis. Antimicrob Agents Chemother 52:4503–4506

    PubMed  CAS  Google Scholar 

  • Grondin K et al (1997) Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J 16:3057–3065

    PubMed  CAS  Google Scholar 

  • Guimond C et al (2003) Modulation of gene expression in Leishmania drug resistant mutants as determined by targeted DNA microarrays. Nucleic Acids Res 31:5886–5896

    PubMed  CAS  Google Scholar 

  • Gygi SP et al (2000) Evaluation of two-dimensional gel electrophoresis-based proteome analysis technology. Proc Natl Acad Sci USA 97:9390–9395

    PubMed  CAS  Google Scholar 

  • Hadighi R et al (2006) Unresponsiveness to Glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites. PLoS Med 3:e162

    PubMed  Google Scholar 

  • Haile S, Papadopoulou B (2007) Developmental regulation of gene expression in trypanosomatid parasitic protozoa. Curr Opin Microbiol 10:569–577

    PubMed  CAS  Google Scholar 

  • Haimeur A et al (1999) Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite-resistant Leishmania. Mol Microbiol 34:726–735

    PubMed  CAS  Google Scholar 

  • Haimeur A et al (2000) Amplification of the ABC transporter gene PGPA and increased trypanothione levels in potassium antimonyl tartrate (SbIII) resistant Leishmania tarentolae. Mol Biochem Parasitol 108:131–135

    PubMed  CAS  Google Scholar 

  • Handman E, Mitchell GF, Goding JW (1981) Identification and characterization of protein antigens of Leishmania tropica isolates. J Immunol 126:508–512

    PubMed  CAS  Google Scholar 

  • Hide M et al (2008) Leishmania infantum: tuning digitonin fractionation for comparative proteomic of the mitochondrial protein content. Parasitol Res 103:989–992

    PubMed  CAS  Google Scholar 

  • Holzer TR, McMaster WR, Forney JD (2006) 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 146:198–218

    PubMed  CAS  Google Scholar 

  • Holzer TR et al (2008) Coordinate regulation of a family of promastigote-enriched mRNAs by the 3′UTR PRE element in Leishmania mexicana. Mol Biochem Parasitol 157:54–64

    PubMed  CAS  Google Scholar 

  • Ivens AC et al (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 309:436–442

    PubMed  Google Scholar 

  • Jardim A et al (1995) Cloning and structure-function analysis of the Leishmania donovani kinetoplastid membrane protein-11. Biochem J 305:315–320

    PubMed  CAS  Google Scholar 

  • Junqueira M et al (2008) Separating the wheat from the chaff: unbiased filtering of background tandem mass spectra improves protein identification. J Proteome Res 7:3382–3395

    PubMed  CAS  Google Scholar 

  • Karas M, Hillemkamp F (1988) Laser desorption ionization of proteins with molecular masses exceeding 10000 KDa. Anal Chem 60:2299–2301

    PubMed  CAS  Google Scholar 

  • Kuhlencord A et al (1992) Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice. Antimicrob Agents Chemother 36:1630–1634

    PubMed  CAS  Google Scholar 

  • Kumar A et al (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 70:609–617

    PubMed  CAS  Google Scholar 

  • Lee MG et al (1988) Structure and expression of the hsp 70 gene family of Leishmania major. Nucleic Acids Res 16:9567–9585

    PubMed  CAS  Google Scholar 

  • Lee N et al (2002) Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death Differ 9:53–64

    PubMed  CAS  Google Scholar 

  • Légaré D et al (2001) The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J Biol Chem 276:26301–26307

    PubMed  Google Scholar 

  • Leifso K et al (2007) Genomic and proteomic expression analysis of Leishmania promastigote and amastigote life stages: the Leishmania genome is constitutively expressed. Mol Biochem Parasitol 152:35–46

    PubMed  CAS  Google Scholar 

  • Leprohon P et al (2006) Modulation of Leishmania ABC protein gene expression through life stages and among drug-resistant parasites. Eukaryot Cell 5:1713–1725

    PubMed  CAS  Google Scholar 

  • Leprohon P et al (2009) Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum. Nucleic Acids Res 37:1387–1399

    PubMed  CAS  Google Scholar 

  • Link AJ et al (1999) Direct analysis of protein complexes using mass spectrometry. Nat Biotechnol 17:676–682

    PubMed  CAS  Google Scholar 

  • Lira R et al (1999) 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 180:564–567

    PubMed  CAS  Google Scholar 

  • Lye LF et al (2010) Retention and loss of RNA interference pathways in trypanosomatid protozoans. PLoS Pathog 6:e1001161

    PubMed  Google Scholar 

  • MacGillivray AJ, Rickwood D (1974) The heterogeneity of mouse-chromatin nonhistone proteins as evidenced by two-dimensional polyacrylamide-gel electrophoresis and ion-exchange chromatography. Eur J Biochem 41:181–190

    PubMed  CAS  Google Scholar 

  • Marquis N et al (2005) Modulation in aquaglyceroporin AQP1 gene transcript levels in drug-resistant Leishmania. Mol Microbiol 57:1690–1699

    PubMed  CAS  Google Scholar 

  • Matsudaira PT (1987) Sequence from picomole quantities of proteins electroblotted onto polyvinylidene difluoride membranes. J Biol Chem 262:10035–10038

    PubMed  CAS  Google Scholar 

  • McNicoll F et al (2006) A combined proteomic and transcriptomic approach to the study of stage differentiation in Leishmania infantum. Proteomics 6:3567–3581

    PubMed  CAS  Google Scholar 

  • Mittal MK et al (2007) Characterization of natural antimony resistance in Leishmania donovani isolates. Am J Trop Med Hyg 76:681–688

    PubMed  CAS  Google Scholar 

  • Mojtahedi Z, Clos J, Kamali-Sarvestani E (2008) Leishmania major: identification of developmentally regulated proteins in procyclic and metacyclic promastigotes. Exp Parasitol 119:422–429

    PubMed  CAS  Google Scholar 

  • Montero-Lomelí M et al (2002) The initiation factor eIF4A is involved in the response to lithium stress in Saccharomyces cerevisiae. J Biol Chem 277:21542–21548

    PubMed  Google Scholar 

  • Morales MA et al (2008) Phosphoproteomic analysis of Leishmania donovani pro- and amastigote stages. Proteomics 8:350–363

    PubMed  CAS  Google Scholar 

  • Mukherjee A et al (2007) Role of ABC transporter MRPA, gamma-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. J Antimicrob Chemother 59:204–211

    PubMed  CAS  Google Scholar 

  • Mukhopadhyay R et al (1996) Trypanothione overproduction and resistance to antimonials and arsenicals in Leishmania. Proc Natl Acad Sci USA 93:10383–10387

    PubMed  CAS  Google Scholar 

  • Mukhopadhyay R et al (2009) Structural characterization of the As/Sb reductase LmACR2 from Leishmania major. J Mol Biol 386:1229–1239

    PubMed  CAS  Google Scholar 

  • Murray HW et al (2005) Advances in leishmaniasis. Lancet 366:1561–1577

    PubMed  CAS  Google Scholar 

  • Navin TR et al (1992) Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 165:528–534

    PubMed  CAS  Google Scholar 

  • Nugent PG et al (2004) Proteomic analysis of Leishmania mexicana differentiation. Mol Biochem Parasitol 136:51–62

    PubMed  CAS  Google Scholar 

  • O’Farrell PH (1975) High resolution two-dimensional electrophoresis of proteins. J Biol Chem 250:4007–4021

    PubMed  Google Scholar 

  • Ouellette M, Borst P (1991) Drug resistance and P-glycoprotein gene amplification in the protozoan parasite Leishmania. Res Microbiol 142:737–746

    PubMed  CAS  Google Scholar 

  • Ouellette M et al (1991) Direct and inverted DNA repeats associated with P-glycoprotein gene amplification in drug resistant Leishmania. EMBO J 10:1009–1016

    PubMed  CAS  Google Scholar 

  • Ouellette M, Drummelsmith J, Papadopoulou B (2004) Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist Updat 7:257–266

    PubMed  CAS  Google Scholar 

  • Paape D et al (2008) Transgenic, fluorescent Leishmania mexicana allow direct analysis of the proteome of intracellular amastigotes. Mol Cell Proteomics 7:1688–1701

    PubMed  CAS  Google Scholar 

  • Palacios R et al (2001) 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 64:187–193

    PubMed  CAS  Google Scholar 

  • Pandey BD et al (2009) Relapse of visceral leishmaniasis after Miltefosine treatment in a Nepalese patient. Am J Trop Med Hyg 80:580–582

    PubMed  Google Scholar 

  • Paris C et al (2004) Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrob Agents Chemother 48:852–859

    PubMed  CAS  Google Scholar 

  • Parodi-Talice A et al (2004) Proteome analysis of the causative agent of Chagas disease: Trypanosoma cruzi. Int J Parasitol 34:881–886

    PubMed  CAS  Google Scholar 

  • Peacock CS et al (2007) Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nat Genet 39:839–847

    PubMed  CAS  Google Scholar 

  • Pérez-Victoria FJ et al (2006a) Phospholipid translocation and Miltefosine potency require both L. donovani Miltefosine transporter and the new protein LdRos3 in Leishmania parasites. J Biol Chem 281:23766–23775

    PubMed  Google Scholar 

  • Pérez-Victoria FJ et al (2006b) Mechanisms of experimental resistance of Leishmania to Miltefosine: implications for clinical use. Drug Resist Updat 9:26–39

    PubMed  Google Scholar 

  • Prasad V, Kaur J, Dey CS (2000) Arsenite-resistant Leishmania donovani promastigotes express an enhanced membrane P-type adenosine triphosphatase activity that is sensitive to verapamil treatment. Parasitol Res 86:661–664

    PubMed  CAS  Google Scholar 

  • Quijada L et al (1997) Analysis of post-transcriptional regulation operating on transcription products of the tandemly linked Leishmania infantum hsp70 genes. J Biol Chem 272:4493–4499

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Rabilloud T et al (2010) Two-dimensional gel electrophoresis in proteomics: past, present and future. J Proteomics 73:2064–2077

    PubMed  CAS  Google Scholar 

  • Rakotomanga M et al (2007) Miltefosine affects lipid metabolism in Leishmania donovani promastigotes. Antimicrob Agents Chemother 51:1425–1430

    PubMed  CAS  Google Scholar 

  • Richard D, Kündig C, Ouellette M (2002) 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 277:29460–29467

    PubMed  CAS  Google Scholar 

  • Rochette A et al (2008) Genome-wide gene expression profiling analysis of Leishmania major and Leishmania infantum developmental stages reveals substantial differences between the two species. BMC Genomics 9:255

    PubMed  Google Scholar 

  • Rojas R et al (2006) Resistance to antimony and treatment failure in human Leishmania (Viannia) infection. J Infect Dis 193:1375–1383

    PubMed  CAS  Google Scholar 

  • Rosenzweig D et al (2008a) Retooling Leishmania metabolism: from sand fly gut to human macrophage. FASEB J 22:590–602

    PubMed  CAS  Google Scholar 

  • Rosenzweig D et al (2008b) Post-translational modification of cellular proteins during Leishmania donovani differentiation. Proteomics 8:1843–1850

    PubMed  CAS  Google Scholar 

  • Sánchez-Cañete MP et al (2009) Low plasma membrane expression of the Miltefosine transport complex renders Leishmania braziliensis refractory to the drug. Antimicrob Agents Chemother 53:1305–1313

    PubMed  Google Scholar 

  • Saravia NG et al (1984) Two-dimensional electrophoresis used to differentiate the causal agents of American tegumentary leishmaniasis. Clin Chem 30:2048–2052

    PubMed  CAS  Google Scholar 

  • Saxena A et al (2003) Evaluation of differential gene expression in Leishmania major Friedlin procyclics and metacyclics using DNA microarray analysis. Mol Biochem Parasitol 129:103–114

    PubMed  CAS  Google Scholar 

  • Saxena A et al (2007) Analysis of the Leishmania donovani transcriptome reveals an ordered progression of transient and permanent changes in gene expression during differentiation. Mol Biochem Parasitol 152:53–65

    PubMed  CAS  Google Scholar 

  • Sereno D et al (2001) Antimonial-mediated DNA fragmentation in Leishmania infantum amastigotes. Antimicrob Agents Chemother 45:2064–2069

    PubMed  CAS  Google Scholar 

  • Shaked-Mishan P et al (2001) Novel intracellular SbV reducing activity correlates with antimony susceptibility in Leishmania donovani. J Biol Chem 276:3971–3976

    PubMed  CAS  Google Scholar 

  • Sharma S et al (2009) Proteomic analysis of wild type and arsenite-resistant Leishmania donovani. Exp Parasitol 123:369–376

    PubMed  CAS  Google Scholar 

  • Silverman JM et al (2008) Proteomic analysis of the secretome of Leishmania donovani. Genome Biol 9:R35

    PubMed  Google Scholar 

  • Singh G, Chavan HD, Dey CS (2008a) Proteomic analysis of Miltefosine-resistant Leishmania reveals the possible involvement of eukaryotic initiation factor 4A (eIF4A). Int J Antimicrob Agents 31:584–586

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Soto J, Soto P (2006) Miltefosine: oral treatment of leishmaniasis. Expert Rev Anti Infect Ther 4:177–185

    PubMed  CAS  Google Scholar 

  • Sudhandiran G, Shaha C (2003) 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 278:25120–25132

    PubMed  CAS  Google Scholar 

  • Sundar S (2001) Drug resistance in Indian visceral leishmaniasis. Trop Med Int Health 6:849–854

    PubMed  CAS  Google Scholar 

  • Sundar S et al (2000) Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic. Clin Infect Dis 31:1104–1107

    PubMed  CAS  Google Scholar 

  • Sundar S et al (2002) Oral Miltefosine for Indian visceral leishmaniasis. N Engl J Med 347:1739–1746

    PubMed  CAS  Google Scholar 

  • Sundar S et al (2008) 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 13:2–5

    PubMed  Google Scholar 

  • Tanaka K et al (1988) Protein and polymer analyses up to m/z 100000 by laser ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 2:151–153

    CAS  Google Scholar 

  • Taylor J et al (1982) Design and implementation of a prototype human protein index. Clin Chem 28:861–866

    PubMed  CAS  Google Scholar 

  • Thakur CP et al (1998) 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 92:561–569

    PubMed  CAS  Google Scholar 

  • Thiel M, Bruchhaus I (2001) Comparative proteome analysis of Leishmania donovani at different stages of transformation from promastigotes to amastigotes. Med Microbiol Immunol 190:33–36

    PubMed  CAS  Google Scholar 

  • Tsukaguchi H et al (1998) Molecular characterization of a broad selectivity neutral solute channel. J Biol Chem 273:24737–24743

    PubMed  CAS  Google Scholar 

  • Ubeda JM et al (2008) Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biol 9:R115

    PubMed  Google Scholar 

  • van Blitterswijk WJ, Verheij M (2008) Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des 14:2061–2074

    PubMed  Google Scholar 

  • Vergnes B et al (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 6:88–101

    PubMed  CAS  Google Scholar 

  • Walker J et al (2006) Identification of developmentally-regulated proteins in Leishmania panamensis by proteome profiling of promastigotes and axenic amastigotes. Mol Biochem Parasitol 147:64–73

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Washburn MP, Wolters D, Yates JR III (2001) Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol 19:242–247

    PubMed  CAS  Google Scholar 

  • World Health Organization (2005) Regional strategic framework for elimination of kala-azar from the South-East Asia region (2005–2015). WHO Regional Office for South-East Asia, New Delhi

    Google Scholar 

  • 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 279:39925–39932

    PubMed  CAS  Google Scholar 

  • Zerpa O et al (2007) Diffuse cutaneous leishmaniasis responds to Miltefosine but then relapses. Br J Dermatol 156:1328–1335

    PubMed  CAS  Google Scholar 

  • Zhou Y et al (2004) Leishmania major LmACR2 is a pentavalent antimony reductase that confers sensitivity to the drug pentostam. J Biol Chem 279:37445–37451

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratório de Pesquisa em Leishmaniose, Instituto Oswaldo Cruz – FIOCRUZ, Av. Brazil 4365, Manguinhos, 21045-900, Rio de Janeiro, RJ, Brazil

    Patricia Cuervo

  2. Laboratorio de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ, Brazil

    Jose Batista de Jesus

  3. Departamento de Engenharia de Biossistemas, Universidade Federal de São João del Rei, São João del Rei, MG, Brazil

    Jose Batista de Jesus

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  1. Patricia Cuervo
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  2. Jose Batista de Jesus
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Correspondence to Patricia Cuervo .

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Editors and Affiliations

  1. Fac. Medicina, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas, 1062, Venezuela

    Alicia Ponte-Sucre

  2. Universidad Central de Venezuela, ciudad universitaria, Caracas, 1062, Venezuela

    Emilia Diaz

  3. Universidad Central de Venezuela, ciudad universitaria, Caracas, 1062, Venezuela

    Maritza Padrón-Nieves

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Cuervo, P., de Jesus, J.B. (2013). Genetic Expression and Drug Resistance, the Role of Proteomics. In: Ponte-Sucre, A., Diaz, E., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1125-3_11

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