Skip to main content
SpringerLink
Log in
Book cover

Drug Resistance in Leishmania Parasites pp 247–272Cite as

The Role of ABC Transporters in Drug-Resistant Leishmania

  • Chapter
  • First Online:

Abstract

The ATP-binding cassette (ABC) transporters belong to the largest family of transmembrane proteins found in living organisms. These proteins are present in prokaryotes and eukaryotes and are mainly involved in the transport of a variety of molecules across cellular membranes, whereas others are involved in biological processes unrelated to transport. The genome sequencing of several Leishmania species confirmed the presence of members for all eight different subfamilies of ABC transporters (ABCA to ABCH), according to their specific functional and molecular characteristics. These proteins have recently been characterized in Leishmania; some of them associated with drug resistance, which is a significant field in leishmaniasis chemotherapy, a disease still lacking effective treatment, with increasing daily reports of therapeutic failure. In this chapter, we focus our discussion on the association of these proteins with drug resistance in leishmaniasis and its fundamental role in the pathology and pharmacology of this medically important protozoan parasite that currently infects around 12 million people in the world.

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

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

Learn about institutional subscriptions

References

  1. Akopyants NS, Kimblin N, Secundino N, Patrick R, et al. Demonstration of genetic exchange during cyclical development of Leishmania in the sand fly vector. Science. 2009;324:265–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Higgins CF. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113.

    Article  PubMed  CAS  Google Scholar 

  3. Saurin W, Hofnung M, Dassa E. Getting in or out: early segregation between importers and exporters in the evolution of ATP-binding cassette (ABC) transporters. J Mol Evol. 1999;48:22–41.

    Article  PubMed  CAS  Google Scholar 

  4. Sauvage V, Aubert D, Escotte-Binet S, Villena I. The role of ATP-binding cassette (ABC) proteins in protozoan parasites. Mol Biochem Parasitol. 2009;167:81–94.

    Article  PubMed  CAS  Google Scholar 

  5. Ouellette M, Fase-Fowler F, Borst P. The amplified H circle of methotrexate-resistant Leishmania tarentolae contains a novel P-glycoprotein gene. EMBO J. 1990;9:1027–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Klokouzas A, Shahi S, Hladky SB, Barrand MA, et al. ABC transporters and drug resistance in parasitic protozoa. Int J Antimicrob Agents. 2003;22:301–17.

    Article  PubMed  CAS  Google Scholar 

  7. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58.

    Article  PubMed  CAS  Google Scholar 

  8. Walker JE, Saraste M, Runswick MJ, Gay NJ. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1982;1:945–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137–71.

    Article  PubMed  CAS  Google Scholar 

  10. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993;62:385–427.

    Article  PubMed  CAS  Google Scholar 

  11. Leprohon P, Legare 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 

  12. Leprohon P, Legare D, Ouellette M. Intracellular localization of the ABCC proteins of Leishmania and their role in resistance to antimonials. Antimicrob Agents Chemother. 2009;53:2646–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Allikmets R, Gerrard B, Hutchinson A, Dean M. Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum Mol Genet. 1996;5:1649–55.

    Article  PubMed  CAS  Google Scholar 

  14. Araujo-Santos JM, Parodi-Talice A, Castanys S, Gamarro F. The overexpression of an intracellular ABCA-like transporter alters phospholipid trafficking in Leishmania. Biochem Biophys Res Commun. 2005;330:349–55.

    Article  PubMed  CAS  Google Scholar 

  15. Castanys-Munoz E, Alder-Baerens N, Pomorski T, Gamarro F, et al. A novel ATP-binding cassette transporter from Leishmania is involved in transport of phosphatidylcholine analogues and resistance to alkyl-phospholipids. Mol Microbiol. 2007;64:1141–53.

    Article  PubMed  CAS  Google Scholar 

  16. Coelho AC, Beverley SM, Cotrim PC. Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major. Mol Biochem Parasitol. 2003;130:83–90.

    Article  PubMed  CAS  Google Scholar 

  17. El Fadili K, Messier N, Leprohon P, Roy G, et al. Role of the ABC transporter MRPA (PGPA) in antimony resistance in Leishmania infantum axenic and intracellular amastigotes. Antimicrob Agents Chemother. 2005;49:1988–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Parodi-Talice A, Araujo JM, Torres C, Perez-Victoria JM, et al. The overexpression of a new ABC transporter in Leishmania is related to phospholipid trafficking and reduced infectivity. Biochim Biophys Acta. 2003;1612:195–207.

    Article  PubMed  CAS  Google Scholar 

  19. 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 

  20. Real F, Vidal RO, Carazzolle MF, Mondego JM, et al. The genome sequence of Leishmania (Leishmania) amazonensis: functional annotation and extended analysis of gene models. DNA Res. 2013;20:567–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 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 

  22. Ivens AC, Lewis SM, Bagherzadeh A, Zhang L, et al. A physical map of the Leishmania major Friedlin genome. Genome Res. 1998;8:135–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Legare D, Hettema E, Ouellette M. The P-glycoprotein-related gene family in Leishmania. Mol Biochem Parasitol. 1994;68:81–91.

    Article  PubMed  CAS  Google Scholar 

  24. Momen H. Some current problems in the systematics of Trypanosomatids. Int J Parasitol. 2001;31:640–2.

    Article  PubMed  CAS  Google Scholar 

  25. Stevens JR, Noyes HA, Schofield CJ, Gibson W. The molecular evolution of Trypanosomatidae. Adv Parasitol. 2001;48:1–56.

    Article  PubMed  CAS  Google Scholar 

  26. 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 

  27. 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 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Albrecht C, Viturro E. The ABCA subfamily—gene and protein structures, functions and associated hereditary diseases. Pflugers Arch. 2007;453:581–9.

    Article  PubMed  CAS  Google Scholar 

  30. 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 

  31. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst. 2000;92:1295–302.

    Article  PubMed  CAS  Google Scholar 

  32. Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001;11:1156–66.

    Article  PubMed  CAS  Google Scholar 

  33. Torres C, Perez-Victoria FJ, Parodi-Talice A, Castanys S, et al. Characterization of an ABCA-like transporter involved in vesicular trafficking in the protozoan parasite Trypanosoma cruzi. Mol Microbiol. 2004;54:632–46.

    Article  PubMed  CAS  Google Scholar 

  34. Henderson DM, Sifri CD, Rodgers M, Wirth DF, et al. Multidrug resistance in Leishmania donovani is conferred by amplification of a gene homologous to the mammalian mdr1 gene. Mol Cell Biol. 1992;12:2855–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Herget M, Tampe R. Intracellular peptide transporters in human--compartmentalization of the “peptidome”. Pflugers Arch. 2007;453:591–600.

    Article  PubMed  CAS  Google Scholar 

  36. Katakura K, Iwanami M, Ohtomo H, Fujise H, et al. Structural and functional analysis of the LaMDR1 multidrug resistance gene in Leishmania amazonensis. Biochem Biophys Res Commun. 1999;255:289–94.

    Article  PubMed  CAS  Google Scholar 

  37. Mitsuhashi N, Miki T, Senbongi H, Yokoi N, et al. MTABC3, a novel mitochondrial ATP-binding cassette protein involved in iron homeostasis. J Biol Chem. 2000;275:17536–40.

    Article  PubMed  CAS  Google Scholar 

  38. Sundaram P, Echalier B, Han W, Hull D, et al. ATP-binding cassette transporters are required for efficient RNA interference in Caenorhabditis elegans. Mol Biol Cell. 2006;17:3678–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Chow LM, Wong AK, Ullman B, Wirth DF. Cloning and functional analysis of an extrachromosomally amplified multidrug resistance-like gene in Leishmania enriettii. Mol Biochem Parasitol. 1993;60:195–208.

    Article  PubMed  CAS  Google Scholar 

  40. Hendrickson N, Sifri CD, Henderson DM, Allen T, et al. Molecular characterization of the ldmdr1 multidrug resistance gene from Leishmania donovani. Mol Biochem Parasitol. 1993;60:53–64.

    Article  PubMed  CAS  Google Scholar 

  41. Katakura K, Fujise H, Takeda K, Kaneko O, et al. Overexpression of LaMDR2, a novel multidrug resistance ATP-binding cassette transporter, causes 5-fluorouracil resistance in Leishmania amazonensis. FEBS Lett. 2004;561:207–12.

    Article  PubMed  CAS  Google Scholar 

  42. Perez-Victoria JM, Parodi-Talice A, Torres C, Gamarro F, et al. ABC transporters in the protozoan parasite Leishmania. Int Microbiol. 2001;4:159–66.

    PubMed  CAS  Google Scholar 

  43. Gueiros-Filho FJ, Viola JP, Gomes FC, Farina M, et al. Leishmania amazonensis: multidrug resistance in vinblastine-resistant promastigotes is associated with rhodamine 123 efflux, DNA amplification, and RNA overexpression of a Leishmania mdr1 gene. Exp Parasitol. 1995;81:480–90.

    Article  PubMed  CAS  Google Scholar 

  44. Chiquero MJ, Perez-Victoria JM, O’valle F, Gonzalez-Ros JM, et al. Altered drug membrane permeability in a multidrug-resistant Leishmania tropica line. Biochem Pharmacol. 1998;55:131–9.

    Article  PubMed  CAS  Google Scholar 

  45. Dodge MA, Waller RF, Chow LM, Zaman MM, et al. Localization and activity of multidrug resistance protein 1 in the secretory pathway of Leishmania parasites. Mol Microbiol. 2004;51:1563–75.

    Article  PubMed  CAS  Google Scholar 

  46. 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 

  47. Legare 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  CAS  Google Scholar 

  48. Papadopoulou B, Roy G, Dey S, Rosen BP, et al. Contribution of the Leishmania P-glycoprotein-related gene ltpgpA to oxyanion resistance. J Biol Chem. 1994;269:11980–6.

    PubMed  CAS  Google Scholar 

  49. Leprohon P, Legare D, Raymond F, Madore E, 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 

  50. Coelho AC, Messier N, Ouellette M, Cotrim PC. Role of the ABC transporter PRP1 (ABCC7) in pentamidine resistance in Leishmania amastigotes. Antimicrob Agents Chemother. 2007;51:3030–2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Coelho AC, Yamashiro-Kanashiro EH, Bastos SF, Mortara RA, et al. Intracellular location of the ABC transporter PRP1 related to pentamidine resistance in Leishmania major. Mol Biochem Parasitol. 2006;150:378–83.

    Article  PubMed  CAS  Google Scholar 

  52. Perea A, Manzano JI, Castanys S, Gamarro F. The LABCG2 transporter from the protozoan parasite Leishmania is involved in antimony resistance. Antimicrob Agents Chemother. 2016;60:3489–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Bosedasgupta S, Ganguly A, Roy A, Mukherjee T, et al. A novel ATP-binding cassette transporter, ABCG6 is involved in chemoresistance of Leishmania. Mol Biochem Parasitol. 2008;158:176–88.

    Article  PubMed  CAS  Google Scholar 

  54. Castanys-Munoz E, Perez-Victoria JM, Gamarro F, Castanys S. Characterization of an ABCG-like transporter from the protozoan parasite Leishmania with a role in drug resistance and transbilayer lipid movement. Antimicrob Agents Chemother. 2008;52:3573–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Manzano JI, Garcia-Hernandez R, Castanys S, Gamarro F. A new ABC half-transporter in Leishmania major is involved in resistance to antimony. Antimicrob Agents Chemother. 2013;57:3719–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Lee JS, Paull K, Alvarez M, Hose C, et al. Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 1994;46:627–38.

    PubMed  CAS  Google Scholar 

  57. Perez-Victoria JM, Perez-Victoria FJ, Parodi-Talice A, Jimenez IA, et al. Alkyl-lysophospholipid resistance in multidrug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator. Antimicrob Agents Chemother. 2001;45:2468–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Seifert K, Matu S, Javier Perez-Victoria F, Castanys S, et al. Characterisation of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int J Antimicrob Agents. 2003;22:380–7.

    Article  PubMed  CAS  Google Scholar 

  59. Jha TK, Sundar S, Thakur CP, Bachmann P, et al. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med. 1999;341:1795–800.

    Article  PubMed  CAS  Google Scholar 

  60. Soto J, Toledo J, Gutierrez P, Nicholls RS, et al. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin Infect Dis. 2001;33:E57–61.

    Article  PubMed  CAS  Google Scholar 

  61. Lux H, Heise N, Klenner T, Hart D, et al. Ether–lipid (alkyl-phospholipid) metabolism and the mechanism of action of ether–lipid analogues in Leishmania. Mol Biochem Parasitol. 2000;111:1–14.

    Article  PubMed  CAS  Google Scholar 

  62. Van Helvoort A, Smith AJ, Sprong H, Fritzsche I, et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell. 1996;87:507–17.

    Article  PubMed  Google Scholar 

  63. Perez-Victoria FJ, Gamarro F, Ouellette M, Castanys S. Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J Biol Chem. 2003;278:49965–71.

    Article  PubMed  CAS  Google Scholar 

  64. Perez-Victoria FJ, Sanchez-Canete 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. 2006;281:23766–75.

    Article  PubMed  CAS  Google Scholar 

  65. Sanchez-Canete MP, Carvalho L, Perez-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 

  66. Basselin M, Denise H, Coombs GH, Barrett, MP. Resistance to pentamidine in Leishmania mexicana involves exclusion of the drug from the mitochondrion. Antimicrob Agents Chemother. 2002;46:3731–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Coelho AC, Gentil LG, Da Silveira JF, Cotrim, PC. Characterization of Leishmania (Leishmania) amazonensis promastigotes resistant to pentamidine. Exp Parasitol. 2008;120:98–102.

    Article  PubMed  CAS  Google Scholar 

  68. Mukherjee A, Padmanabhan PK, Sahani MH, Barrett MP, et al. Roles for mitochondria in pentamidine susceptibility and resistance in Leishmania donovani. Mol Biochem Parasitol. 2006;145:1–10.

    Article  PubMed  CAS  Google Scholar 

  69. Bitonti AJ, Sjoerdsma A, Mccann PP, Kyle DE, et al. Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine. Science. 1988;242:1301–3.

    Article  PubMed  CAS  Google Scholar 

  70. Wong IL, Chow LM. The role of Leishmania enriettii multidrug resistance protein 1 (LeMDR1) in mediating drug resistance is iron-dependent. Mol Biochem Parasitol. 2006;150:278–87.

    Article  PubMed  CAS  Google Scholar 

  71. Kispal G, Csere P, Prohl C, Lill R. The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. EMBO J. 1999;18:3981–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Martinez-Garcia M, Campos-Salinas J, Cabello-Donayre M, Pineda-Molina E, et al. LmABCB3, an atypical mitochondrial ABC transporter essential for Leishmania major virulence, acts in heme and cytosolic iron/sulfur clusters biogenesis. Parasit Vectors. 2016;9:7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Deeley RG, Westlake C, Cole SP. Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev. 2006;86:849–99.

    Article  PubMed  CAS  Google Scholar 

  74. Zhou SF, Wang LL, Di YM, Xue CC, et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem. 2008;15:1981–2039.

    Article  PubMed  CAS  Google Scholar 

  75. Pompella A, Visvikis A, Paolicchi A, De Tata V, et al. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol. 2003;66:1499–503.

    Article  PubMed  CAS  Google Scholar 

  76. Ouellette M, Legare D, Haimeur A, Grondin K, et al. ABC transporters in Leishmania and their role in drug resistance. Drug Resist Updat. 1998;1:43–8.

    Article  PubMed  CAS  Google Scholar 

  77. Callahan HL, Beverley SM. A member of the aldoketo reductase family confers methotrexate resistance in Leishmania. J Biol Chem. 1992;267:24165–8.

    PubMed  CAS  Google Scholar 

  78. Papadopoulou B, Roy G, Ouellette M. A novel antifolate resistance gene on the amplified H circle of Leishmania. EMBO J. 1992;11:3601–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Grondin K, Papadopoulou B, Ouellette M. Homologous recombination between direct repeat sequences yields P-glycoprotein containing amplicons in arsenite resistant Leishmania. Nucleic Acids Res. 1993;21:1895–901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. 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 

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

    Article  PubMed  CAS  Google Scholar 

  82. Borst P, Ouellette M. New mechanisms of drug resistance in parasitic protozoa. Annu Rev Microbiol. 1995;49:427–60.

    Article  PubMed  CAS  Google Scholar 

  83. Mary C, Faraut F, Deniau M, Dereure J, et al. Frequency of drug resistance gene amplification in clinical Leishmania strains. Int J Microbiol. 2010;2010:1.

    Article  CAS  Google Scholar 

  84. Mukherjee A, Boisvert S, Monte-Neto RL, Coelho AC, et al. Telomeric gene deletion and intrachromosomal amplification in antimony-resistant Leishmania. Mol Microbiol. 2013;88:189–202.

    Article  PubMed  CAS  Google Scholar 

  85. Papadopoulou B, Roy G, Dey S, Rosen BP, et al. Gene disruption of the P-glycoprotein related gene pgpa of Leishmania tarentolae. Biochem Biophys Res Commun. 1996;224:772–8.

    Article  PubMed  CAS  Google Scholar 

  86. 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 

  87. Fairlamb AH, Cerami A. Metabolism and functions of trypanothione in the Kinetoplastida. Annu Rev Microbiol. 1992;46:695–729.

    Article  PubMed  CAS  Google Scholar 

  88. 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 

  89. Haimeur A, Guimond C, Pilote S, Mukhopadhyay R, 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  PubMed  CAS  Google Scholar 

  90. 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 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Arana FE, Perez-Victoria JM, Repetto Y, Morello A, et al. Involvement of thiol metabolism in resistance to glucantime in Leishmania tropica. Biochem Pharmacol. 1998;56:1201–8.

    Article  PubMed  CAS  Google Scholar 

  93. Legare D, Papadopoulou B, Roy G, Mukhopadhyay R, et al. Efflux systems and increased trypanothione levels in arsenite-resistant Leishmania. Exp Parasitol. 1997;87:275–82.

    Article  PubMed  CAS  Google Scholar 

  94. Dias FC, Ruiz JC, Lopes WC, Squina FM, et al. Organization of H locus conserved repeats in Leishmania (Viannia) braziliensis correlates with lack of gene amplification and drug resistance. Parasitol Res. 2007;101:667–76.

    Article  PubMed  Google Scholar 

  95. 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 

  96. Beverley SM. Protozomics: trypanosomatid parasite genetics comes of age. Nat Rev Genet. 2003;4:11–9.

    Article  PubMed  CAS  Google Scholar 

  97. Kapler GM, Beverley SM. Transcriptional mapping of the amplified region encoding the dihydrofolate reductase-thymidylate synthase of Leishmania major reveals a high density of transcripts, including overlapping and antisense RNAs. Mol Cell Biol. 1989;9:3959–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. 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 

  99. Brotherton MC, Bourassa S, Leprohon P, Legare 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 

  100. 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 

  101. Moreira DS, Monte Neto RL, Andrade JM, Santi AM, et al. Molecular characterization of the MRPA transporter and antimony uptake in four new world Leishmania spp. susceptible and resistant to antimony. Int J Parasitol Drugs Drug Resist. 2014;3:143–53.

    Article  Google Scholar 

  102. Shahi SK, Krauth-Siegel RL, Clayton CE. Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei. Mol Microbiol. 2002;43:1129–38.

    Article  PubMed  CAS  Google Scholar 

  103. Ghedin E, Debrabant A, Engel JC, Dwyer DM. Secretory and endocytic pathways converge in a dynamic endosomal system in a primitive protozoan. Traffic. 2001;2:175–88.

    Article  PubMed  CAS  Google Scholar 

  104. Mcconville MJ, Mullin KA, Ilgoutz SC, Teasdale RD. Secretory pathway of trypanosomatid parasites. Microbiol Mol Biol Rev. 2002;66:122–54. table of contents

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Mullin KA, Foth BJ, Ilgoutz SC, Callaghan JM, et al. Regulated degradation of an endoplasmic reticulum membrane protein in a tubular lysosome in Leishmania mexicana. Mol Biol Cell. 2001;12:2364–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Ellenberger TE, Beverley SM. Multiple drug resistance and conservative amplification of the H region in Leishmania major. J Biol Chem. 1989;264:15094–103.

    PubMed  CAS  Google Scholar 

  107. Leprohon P, Fernandez-Prada C, Gazanion E, Monte-Neto R, et al. Drug resistance analysis by next generation sequencing in Leishmania. Int J Parasitol Drugs Drug Resist. 2015;5:26–35.

    Article  PubMed  Google Scholar 

  108. Dey S, Ouellette M, Lightbody J, Papadopoulou B, et al. An ATP-dependent as(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. Proc Natl Acad Sci U S A. 1996;93:2192–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Dallagiovanna B, Gamarro F, Castanys S. Molecular characterization of a P-glycoprotein-related tcpgp2 gene in Trypanosoma cruzi. Mol Biochem Parasitol. 1996;75:145–57.

    Article  PubMed  CAS  Google Scholar 

  110. Torres C, Barreiro L, Dallagiovanna B, Gamarro F, et al. Characterization of a new ATP-binding cassette transporter in Trypanosoma cruzi associated to a L1Tc retrotransposon. Biochim Biophys Acta. 1999;1489:428–32.

    Article  PubMed  CAS  Google Scholar 

  111. Murta SM, Dos Santos WG, Anacleto C, Nirde P, et al. Drug resistance in Trypanosoma cruzi is not associated with amplification or overexpression of P-glycoprotein (PGP) genes. Mol Biochem Parasitol. 2001;117:223–8.

    Article  PubMed  CAS  Google Scholar 

  112. Mittal MK, Rai S, Gupta S, Ravinder, 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 

  113. Singh N, Singh RT, Sundar S. Novel mechanism of drug resistance in kala azar field isolates. J Infect Dis. 2003;188:600–7.

    Article  PubMed  CAS  Google Scholar 

  114. 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 

  115. Velamakanni S, Wei SL, Janvilisri T, Van Veen HW. ABCG transporters: structure, substrate specificities and physiological roles : a brief overview. J Bioenerg Biomembr. 2007;39:465–71.

    Article  PubMed  CAS  Google Scholar 

  116. Ejendal KF, Hrycyna CA. Multidrug resistance and cancer: the role of the human ABC transporter ABCG2. Curr Protein Pept Sci. 2002;3:503–11.

    Article  PubMed  CAS  Google Scholar 

  117. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 2005;204:216–37.

    Article  PubMed  CAS  Google Scholar 

  118. Bories C, Cojean S, Huteau F, Loiseau PM. Selection and phenotype characterisation of sitamaquine-resistant promastigotes of Leishmania donovani. Biomed Pharmacother. 2008;62:164–7.

    Article  PubMed  CAS  Google Scholar 

  119. Zingales B, Araujo RG, Moreno M, Franco J, et al. A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole. Mem Inst Oswaldo Cruz. 2015;110:433–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Hettema EH, Van Roermund CW, Distel B, Van Den Berg M, et al. The ABC transporter proteins Pat1 and Pat2 are required for import of long-chain fatty acids into peroxisomes of Saccharomyces cerevisiae. EMBO J. 1996;15:3813–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Theodoulou FL, Holdsworth M, Baker A. Peroxisomal ABC transporters. FEBS Lett. 2006;580:1139–55.

    Article  PubMed  CAS  Google Scholar 

  122. Shani N, Valle D. Peroxisomal ABC transporters. Methods Enzymol. 1998;292:753–76.

    Article  PubMed  CAS  Google Scholar 

  123. Petriv OI, Pilgrim DB, Rachubinski RA, Titorenko VI. RNA interference of peroxisome-related genes in C. elegans: a new model for human peroxisomal disorders. Physiol Genomics. 2002;10:79–91.

    Article  PubMed  CAS  Google Scholar 

  124. Michels PA, Bringaud F, Herman M, Hannaert V. Metabolic functions of glycosomes in trypanosomatids. Biochim Biophys Acta. 2006;1763:1463–77.

    Article  PubMed  CAS  Google Scholar 

  125. Kerr ID. Sequence analysis of twin ATP binding cassette proteins involved in translational control, antibiotic resistance, and ribonuclease L inhibition. Biochem Biophys Res Commun. 2004;315:166–73.

    Article  PubMed  CAS  Google Scholar 

  126. Dean M, Annilo T. Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates. Annu Rev Genomics Hum Genet. 2005;6:123–42.

    Article  PubMed  CAS  Google Scholar 

  127. Zhou A, Hassel BA, Silverman RH. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell. 1993;72:753–65.

    Article  PubMed  CAS  Google Scholar 

  128. Chen ZQ, Dong J, Ishimura A, Daar I, et al. The essential vertebrate ABCE1 protein interacts with eukaryotic initiation factors. J Biol Chem. 2006;281:7452–7.

    Article  PubMed  CAS  Google Scholar 

  129. Estevez AM, Haile S, Steinbuchel M, Quijada L, et al. Effects of depletion and overexpression of the Trypanosoma brucei ribonuclease L inhibitor homologue. Mol Biochem Parasitol. 2004;133:137–41.

    Article  PubMed  CAS  Google Scholar 

  130. Tyzack JK, Wang X, Belsham GJ, Proud CG. ABC50 interacts with eukaryotic initiation factor 2 and associates with the ribosome in an ATP-dependent manner. J Biol Chem. 2000;275:34131–9.

    Article  PubMed  CAS  Google Scholar 

  131. Marton MJ, Vazquez De Aldana CR, Qiu H, Chakraburtty K, et al. Evidence that GCN1 and GCN20, translational regulators of GCN4, function on elongating ribosomes in activation of eIF2alpha kinase GCN2. Mol Cell Biol. 1997;17:4474–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Sandbaken MG, Lupisella JA, Didomenico B, Chakraburtty K. Protein synthesis in yeast. Structural and functional analysis of the gene encoding elongation factor 3. J Biol Chem. 1990;265:15838–44.

    PubMed  CAS  Google Scholar 

  133. 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 

  134. Manzano JI, Lecerf-Schmidt F, Lespinasse MA, Di Pietro A, et al. Identification of specific reversal agents for Leishmania ABCI4-mediated antimony resistance by flavonoid and trolox derivative screening. J Antimicrob Chemother. 2014;69:664–72.

    Article  PubMed  CAS  Google Scholar 

  135. Mookerjee Basu J, Mookerjee A, Banerjee R, Saha M, et al. Inhibition of ABC transporters abolishes antimony resistance in Leishmania infection. Antimicrob Agents Chemother. 2008;52:1080–93.

    Article  PubMed  CAS  Google Scholar 

  136. Ponte-Sucre A. Availability and applications of ATP-binding cassette (ABC) transporter blockers. Appl Microbiol Biotechnol. 2007;76:279–86.

    Article  PubMed  CAS  Google Scholar 

  137. Padron-Nieves M, Diaz E, Machuca C, Romero A, et al. Glibenclamide modulates glucantime activity and disposition in Leishmania major. Exp Parasitol. 2009;121:331–7.

    Article  PubMed  CAS  Google Scholar 

  138. Serrano-Martin X, Payares G, Mendoza-Leon A. Glibenclamide, a blocker of K+(ATP) channels, shows antileishmanial activity in experimental murine cutaneous leishmaniasis. Antimicrob Agents Chemother. 2006;50:4214–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Silva N, Camacho N, Figarella K, Ponte-Sucre A. Cell differentiation and infectivity of Leishmania mexicana are inhibited in a strain resistant to an ABC-transporter blocker. Parasitology. 2004;128:629–34.

    Article  PubMed  CAS  Google Scholar 

  140. Coelho AC, Trinconi CT, Costa CH, Uliana SR. In vitro and in vivo miltefosine susceptibility of a Leishmania amazonensis isolate from a patient with diffuse cutaneous leishmaniasis. PLoS Negl Trop Dis. 2014;8:e2999.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Croft SL, Engel J. Miltefosine--discovery of the antileishmanial activity of phospholipid derivatives. Trans R Soc Trop Med Hyg. 2006;100(Suppl 1):S4–8.

    Article  PubMed  CAS  Google Scholar 

  142. Espada CR, Ribeiro-Dias F, Dorta ML, Pereira LIA, et al. Susceptibility to Miltefosine in Brazilian clinical isolates of Leishmania (Viannia) braziliensis. Am J Trop Med Hyg. 2017;96(3):656–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  143. Kumar D, Kulshrestha A, Singh R, Salotra P. 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. 2009;53:835–8.

    Article  PubMed  CAS  Google Scholar 

  144. Obonaga R, Fernandez OL, Valderrama L, Rubiano LC, et al. Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by Leishmania subgenus Viannia species. Antimicrob Agents Chemother. 2014;58:144–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Prajapati VK, Mehrotra S, Gautam S, Rai M, et al. In vitro antileishmanial drug susceptibility of clinical isolates from patients with Indian visceral leishmaniasis--status of newly introduced drugs. Am J Trop Med Hyg. 2012;87:655–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Prajapati VK, Sharma S, Rai M, Ostyn B, et al. In vitro susceptibility of Leishmania donovani to miltefosine in Indian visceral leishmaniasis. Am J Trop Med Hyg. 2013;89:750–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Utaile M, Kassahun A, Abebe T, Hailu A. Susceptibility of clinical isolates of Leishmania aethiopica to miltefosine, paromomycin, amphotericin B and sodium stibogluconate using amastigote-macrophage in vitro model. Exp Parasitol. 2013;134:68–75.

    Article  PubMed  CAS  Google Scholar 

  148. Zauli-Nascimento RC, Miguel DC, Yokoyama-Yasunaka JK, Pereira LI, et al. In vitro sensitivity of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis Brazilian isolates to meglumine antimoniate and amphotericin B. Trop Med Int Health. 2010;15:68–76.

    PubMed  CAS  Google Scholar 

  149. Clayton CE. Genetic manipulation of kinetoplastida. Parasitol Today. 1999;15(9):372–8.

    Article  PubMed  CAS  Google Scholar 

  150. Ubeda JM, Legare 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 

  151. Coelho AC, Boisvert S, Mukherjee A, Leprohon P, et al. Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. PLoS Negl Trop Dis. 2012;6:e1512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Fernandez-Prada C, Vincent IM, Brotherton MC, Roberts M, et al. Different mutations in a P-type ATPase transporter in Leishmania parasites are associated with cross-resistance to two leading drugs by distinct mechanisms. PLoS Negl Trop Dis. 2016;10:e0005171.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Shaw CD, Lonchamp J, Downing T, Imamura H, et al. In vitro selection of miltefosine resistance in promastigotes of Leishmania donovani from Nepal: genomic and metabolomic characterization. Mol Microbiol. 2016;99:1134–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. 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 

  155. 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 

  156. 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 

  157. Rougeron V, De Meeus T, Hide M, Waleckx E, et al. Extreme inbreeding in Leishmania braziliensis. Proc Natl Acad Sci USA. 2009;106:10224–9.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Glaucia Paranhos for critical reading of the chapter.

Author information

Authors and Affiliations

  1. Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP, Brazil

    Adriano C. Coelho

  2. Departamento de Moléstias Infecciosas e Parasitárias, Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Paulo C. Cotrim

Authors
  1. Adriano C. Coelho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paulo C. Cotrim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paulo C. Cotrim .

Editor information

Editors and Affiliations

  1. Institute of Experimental Medicine, Universidad Central de Venezuela, Caracas, Venezuela

    Alicia Ponte-Sucre

  2. Escuela Luis Razetti Fac de Medicine, Universidad Central de Venezuela, Caracas, Venezuela

    Maritza Padrón-Nieves

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

Coelho, A.C., Cotrim, P.C. (2018). The Role of ABC Transporters in Drug-Resistant Leishmania. 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_11

Download citation

Publish with us

Policies and ethics

Search

Navigation