Skip to main content

Advertisement

SpringerLink
Log in

Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

Miltefosine (MT) (hexadecylphosphocholine) was implemented to cope with resistance against antimonials, the classical treatment in Leishmaniasis. Given the scarcity of anti- Leishmania (L) drugs and the increasing appearance of resistance, there is an obvious need for understanding the mechanism of action and development of such resistance. Metabolomics is an increasingly popular tool in the life sciences due to it being a relatively fast and accurate technique that can be applied either with a particular focus or in a global manner to reveal new knowledge about biological systems. Three analytical platforms, gas chromatography (GC), liquid chromatography (LC) and capillary electrophoresis (CE) have been coupled to mass spectrometry (MS) to obtain a broad picture of metabolic changes in the parasite. Impairment of the polyamine metabolism from arginine (Arg) to trypanothione in susceptible parasites treated with MT was in some way expected, considering the reactive oxygen species (ROS) production described for MT. Importantly, in resistant parasites an increase in the levels of amino acids was the most outstanding feature, probably related to the adaptation of the resistant strain for its survival inside the parasitophorous vacuole.

ᅟ

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Organization WH Technical report series no. 949. In: Control of the leishmaniasis: report of a meeting of the World Health Organization Expert Committee on the Control of Leishmaniases, Geneva, 2010. pp 22–26

  2. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, Team WLC (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS One 7(5):e35671

    Article  CAS  Google Scholar 

  3. Alvar J, Croft SL, Kaye P, Khamesipour A, Sundar S, Reed SG (2013) Case study for a vaccine against leishmaniasis. Vaccine 31(Suppl 2):B244–B249

    Article  CAS  Google Scholar 

  4. Nagill R, Kaur S (2011) Vaccine candidates for leishmaniasis: a review. Int Immunopharmacol 11(10):1464–1488

    Article  CAS  Google Scholar 

  5. Croft SL, Olliaro P (2011) Leishmaniasis chemotherapy–challenges and opportunities. Clin Microbiol Infect 17(10):1478–1483

    Article  CAS  Google Scholar 

  6. van Griensven J, Balasegaram M, Meheus F, Alvar J, Lynen L, Boelaert M (2010) Combination therapy for visceral leishmaniasis. Lancet Infect Dis 10(3):184–194

    Article  Google Scholar 

  7. Sundar S, Chakravarty J (2013) Leishmaniasis: an update of current pharmacotherapy. Expert Opin Pharmacother 14(1):53–63

    Article  CAS  Google Scholar 

  8. Alvar J, Yactayo S, Bern C (2006) Leishmaniasis and poverty. Trends Parasitol 22(12):552–557

    Article  Google Scholar 

  9. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J (2002) Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 347(22):1739–1746

    Article  CAS  Google Scholar 

  10. Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ (2012) Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 67(11):2576–2597

    Article  CAS  Google Scholar 

  11. Kumar D, Kulshrestha A, Singh R, Salotra P (2009) In vitro susceptibility of field isolates of Leishmania donovani to Miltefosine and amphotericin B: correlation with sodium antimony gluconate susceptibility and implications for treatment in areas of endemicity. Antimicrob Agents Chemother 53(2):835–838

    Article  CAS  Google Scholar 

  12. Moreira W, Leprohon P, Ouellette M (2011) Tolerance to drug-induced cell death favours the acquisition of multidrug resistance in Leishmania. Cell Death Dis 2:e201

    Article  CAS  Google Scholar 

  13. Rijal S, Ostyn B, Uranw S, Rai K, Bhattarai NR, Dorlo TP, Beijnen JH, Vanaerschot M, Decuypere S, Dhakal SS, Das ML, Karki P, Singh R, Boelaert M, Dujardin JC (2013) Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance. Clin Infect Dis 56(11):1530–1538

    Article  CAS  Google Scholar 

  14. Sundar S, Chakravarty J (2012) Recent advances in the diagnosis and treatment of kala-azar. Natl Med J India 25(2):85–89

    Google Scholar 

  15. Paris C, Loiseau PM, Bories C, Bréard J (2004) Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrob Agents Chemother 48(3):852–859

    Article  CAS  Google Scholar 

  16. Proto WR, Coombs GH, Mottram JC (2013) Cell death in parasitic protozoa: regulated or incidental? Nat Rev Microbiol 11(1):58–66

    Article  CAS  Google Scholar 

  17. Saugar JM, Delgado J, Hornillos V, Luque-Ortega JR, Amat-Guerri F, Acuña AU, Rivas L (2007) Synthesis and biological evaluation of fluorescent leishmanicidal analogues of hexadecylphosphocholine (miltefosine) as probes of antiparasite mechanisms. J Med Chem 50(24):5994–6003

    Article  CAS  Google Scholar 

  18. Zufferey R, Mamoun CB (2002) Choline transport in Leishmania major promastigotes and its inhibition by choline and phosphocholine analogs. Mol Biochem Parasitol 125(1–2):127–134

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  20. Barratt G, Saint-Pierre-Chazalet M, Loiseau PM (2009) Cellular transport and lipid interactions of miltefosine. Curr Drug Metab 10(3):247–255

    Article  CAS  Google Scholar 

  21. Imbert L, Ramos RG, Libong D, Abreu S, Loiseau PM, Chaminade P (2012) Identification of phospholipid species affected by miltefosine action in Leishmania donovani cultures using LC-ELSD, LC-ESI/MS, and multivariate data analysis. Anal Bioanal Chem 402(3):1169–1182

    Article  CAS  Google Scholar 

  22. Rakotomanga M, Saint-Pierre-Chazalet M, Loiseau PM (2005) Alteration of fatty acid and sterol metabolism in miltefosine-resistant Leishmania donovani promastigotes and consequences for drug-membrane interactions. Antimicrob Agents Chemother 49(7):2677–2686

    Google Scholar 

  23. Getachew F, Gedamu L (2012) Leishmania donovani mitochondrial iron superoxide dismutase A is released into the cytosol during miltefosine induced programmed cell death. Mol Biochem Parasitol 183(1):42–51

    Article  CAS  Google Scholar 

  24. Luque-Ortega JR, Rivas L (2007) Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes. Antimicrob Agents Chemother 51(4):1327–1332

    Article  CAS  Google Scholar 

  25. Zuo X, Djordjevic JT, Bijosono Oei J, Desmarini D, Schibeci SD, Jolliffe KA, Sorrell TC (2011) Miltefosine induces apoptosis-like cell death in yeast via Cox9p in cytochrome c oxidase. Mol Pharmacol 80(3):476–485

    Article  CAS  Google Scholar 

  26. Das M, Saudagar P, Sundar S, Dubey VK (2013) Miltefosine–unresponsive Leishmania donovani has a greater ability than miltefosine–responsive L. donovani to resist reactive oxygen species. FEBS J 280(19):4807–4815

    Article  CAS  Google Scholar 

  27. Mishra J, Singh S (2013) Miltefosine resistance in Leishmania donovani involves suppression of oxidative stress-induced programmed cell death. Exp Parasitol 135(2):397–406

    Article  CAS  Google Scholar 

  28. Pérez-Victoria FJ, Gamarro F, Ouellette M, Castanys S (2003) Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J Biol Chem 278(50):49965–49971

    Article  Google Scholar 

  29. Pérez-Victoria FJ, Castanys S, Gamarro F (2003) Leishmania donovani resistance to miltefosine involves a defective inward translocation of the drug. Antimicrob Agents Chemother 47(8):2397–2403

    Article  Google Scholar 

  30. Pérez-Victoria FJ, Sánchez-Cañete MP, Castanys S, Gamarro F (2006) Phospholipid translocation and miltefosine potency require both L. donovani miltefosine transporter and the new protein LdRos3 in Leishmania parasites. J Biol Chem 281(33):23766–23775

    Article  Google Scholar 

  31. Sánchez-Cañete MP, Carvalho L, Pérez-Victoria FJ, Gamarro F, Castanys S (2009) Low plasma membrane expression of the miltefosine transport complex renders Leishmania braziliensis refractory to the drug. Antimicrob Agents Chemother 53(4):1305–1313

    Article  Google Scholar 

  32. Castanys-Muñoz E, Pérez-Victoria JM, Gamarro F, Castanys S (2008) Characterization of an ABCG-like transporter from the protozoan parasite Leishmania with a role in drug resistance and transbilayer lipid movement. Antimicrob Agents Chemother 52(10):3573–3579

    Article  Google Scholar 

  33. Pérez-Victoria JM, Pérez-Victoria FJ, Parodi-Talice A, Jiménez IA, Ravelo AG, Castanys S, Gamarro F (2001) Alkyl-lysophospholipid resistance in multidrug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator. Antimicrob Agents Chemother 45(9):2468–2474

    Article  Google Scholar 

  34. Coelho AC, Boisvert S, Mukherjee A, Leprohon P, Corbeil J, Ouellette M (2012) Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. PLoS Negl Trop Dis 6(2):e1512

    Article  CAS  Google Scholar 

  35. Cojean S, Houzé S, Haouchine D, Huteau F, Lariven S, Hubert V, Michard F, Bories C, Pratlong F, Le Bras J, Loiseau PM, Matheron S (2012) Leishmania resistance to miltefosine associated with genetic marker. Emerg Infect Dis 18(4):704–706

    Article  Google Scholar 

  36. Bhandari V, Kulshrestha A, Deep DK, Stark O, Prajapati VK, Ramesh V, Sundar S, Schonian G, Dujardin JC, Salotra P (2012) Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis. PLoS Negl Trop Dis 6(5):e1657

    Article  CAS  Google Scholar 

  37. García-Hernández R, Manzano JI, Castanys S, Gamarro F (2012) Leishmania donovani develops resistance to drug combinations. PLoS Negl Trop Dis 6(12):e1974

    Article  Google Scholar 

  38. Xiayan L, Legido-Quigley C (2008) Advances in separation science applied to metabonomics. Electrophoresis 29(18):3724–3736

    Article  Google Scholar 

  39. Smolinska A, Blanchet L, Buydens LM, Wijmenga SS (2012) NMR and pattern recognition methods in metabolomics: from data acquisition to biomarker discovery: a review. Anal Chim Acta 750:82–97

    Article  CAS  Google Scholar 

  40. Barding GA, Salditos R, Larive CK (2012) Quantitative NMR for bioanalysis and metabolomics. Anal Bioanal Chem 404(4):1165–1179

    Article  CAS  Google Scholar 

  41. Putri SP, Yamamoto S, Tsugawa H, Fukusaki E (2013) Current metabolomics: technological advances. J Biosci Bioeng 116(1):9–16

    Article  CAS  Google Scholar 

  42. Barbas C, Moraes EP, Villaseñor A (2011) Capillary electrophoresis as a metabolomics tool for non-targeted fingerprinting of biological samples. J Pharm Biomed Anal 55(4):823–831

    Article  CAS  Google Scholar 

  43. Rojo D, Barbas C, Rupérez FJ (2012) LC-MS metabolomics of polar compounds. Bioanalysis 4(10):1235–1243

    Article  CAS  Google Scholar 

  44. Koek MM, Jellema RH, van der Greef J, Tas AC, Hankemeier T (2011) Quantitative metabolomics based on gas chromatography mass spectrometry: status and perspectives. Metabolomics 7(3):307–328

    Article  CAS  Google Scholar 

  45. Creek DJ, Jankevics A, Breitling R, Watson DG, Barrett MP, Burgess KE (2011) Toward global metabolomics analysis with hydrophilic interaction liquid chromatography-mass spectrometry: improved metabolite identification by retention time prediction. Anal Chem 83(22):8703–8710

    Article  CAS  Google Scholar 

  46. Requena JM (2011) Lights and shadows on gene organization and regulation of gene expression in Leishmania. Front Biosci (Landmark Ed) 16:2069–2085

    Article  CAS  Google Scholar 

  47. Chawla B, Jhingran A, Panigrahi A, Stuart KD, Madhubala R (2011) Paromomycin affects translation and vesicle-mediated trafficking as revealed by proteomics of paromomycin -susceptible -resistant Leishmania donovani. PLoS One 6(10):e26660

    Article  CAS  Google Scholar 

  48. Paape D, Aebischer T (2011) Contribution of proteomics of Leishmania spp. to the understanding of differentiation, drug resistance mechanisms, vaccine and drug development. J Proteomics 74(9):1614–1624

    Article  CAS  Google Scholar 

  49. Vergnes B, Gourbal B, Girard I, Sundar S, Drummelsmith J, Ouellette M (2007) A proteomics screen implicates HSP83 and a small kinetoplastid calpain-related protein in drug resistance in Leishmania donovani clinical field isolates by modulating drug-induced programmed cell death. Mol Cell Proteomics 6(1):88–101

    Article  CAS  Google Scholar 

  50. Doyle MA, MacRae JI, De Souza DP, Saunders EC, McConville MJ, Likić VA (2009) LeishCyc: a biochemical pathways database for Leishmania major. BMC Syst Biol 3:57

    Article  Google Scholar 

  51. Creek DJ, Anderson J, McConville MJ, Barrett MP (2012) Metabolomic analysis of trypanosomatid protozoa. Mol Biochem Parasitol 181(2):73–84

    Article  CAS  Google Scholar 

  52. McConville MJ, Naderer T (2011) Metabolic pathways required for the intracellular survival of Leishmania. Annu Rev Microbiol 65:543–561

    Google Scholar 

  53. Opperdoes FR, Coombs GH (2007) Metabolism of Leishmania: proven and predicted. Trends Parasitol 23(4):149–158

    Article  CAS  Google Scholar 

  54. Scheltema RA, Decuypere S, T'kindt R, Dujardin JC, Coombs GH, Breitling R (2010) The potential of metabolomics for Leishmania research in the post-genomics era. Parasitology 137(9):1291–1302

    Article  CAS  Google Scholar 

  55. Lamour SD, Choi BS, Keun HC, Müller I, Saric J (2012) Metabolic characterization of Leishmania major infection in activated and nonactivated macrophages. J Proteome Res 11(8):4211–4222

    Article  CAS  Google Scholar 

  56. Canuto GA, Castilho-Martins EA, Tavares M, López-Gonzálvez A, Rivas L, Barbas C (2012) CE-ESI-MS metabolic fingerprinting of Leishmania resistance to antimony treatment. Electrophoresis 33(12):1901–1910

    Article  CAS  Google Scholar 

  57. T'Kindt R, Scheltema RA, Jankevics A, Brunker K, Rijal S, Dujardin JC, Breitling R, Watson DG, Coombs GH, Decuypere S (2010) Metabolomics to unveil and understand phenotypic diversity between pathogen populations. PLoS Negl Trop Dis 4(11):e904

    Article  Google Scholar 

  58. Seifert K, Matu S, Javier Pérez-Victoria F, Castanys S, Gamarro F, Croft SL (2003) Characterisation of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int J Antimicrob Agents 22(4):380–387

    Article  CAS  Google Scholar 

  59. Suhre K, Schmitt-Kopplin P (2008) MassTRIX: mass translator into pathways. Nucleic Acids Res 36 (Web Server issue):W481-484.

  60. Jiménez-López JM, Ríos-Marco P, Marco C, Segovia JL, Carrasco MP (2010) Alterations in the homeostasis of phospholipids and cholesterol by antitumor alkylphospholipids. Lipids Health Dis 9:33

    Article  Google Scholar 

  61. Verma NK, Dey CS (2004) Possible mechanism of miltefosine-mediated death of Leishmania donovani. Antimicrob Agents Chemother 48(8):3010–3015

    Article  CAS  Google Scholar 

  62. Rakotomanga M, Blanc S, Gaudin K, Chaminade P, Loiseau PM (2007) Miltefosine affects lipid metabolism in Leishmania donovani promastigotes. Antimicrob Agents Chemother 51(4):1425–1430

    Article  CAS  Google Scholar 

  63. Ramos RG, Libong D, Rakotomanga M, Gaudin K, Loiseau PM, Chaminade P (2008) Comparison between charged aerosol detection and light scattering detection for the analysis of Leishmania membrane phospholipids. J Chromatogr A 1209(1–2):88–94

    Article  CAS  Google Scholar 

  64. Geilen CC, Wieder T, Orfanos CE (1996) Phosphatidylcholine biosynthesis as a target for phospholipid analogues. Adv Exp Med Biol 416:333–336

    Article  CAS  Google Scholar 

  65. Seifert K, Pérez-Victoria FJ, Stettler M, Sánchez-Cañete MP, Castanys S, Gamarro F, Croft SL (2007) Inactivation of the miltefosine transporter, LdMT, causes miltefosine resistance that is conferred to the amastigote stage of Leishmania donovani and persists in vivo. Int J Antimicrob Agents 30(3):229–235

    Article  CAS  Google Scholar 

  66. T'Kindt R, Jankevics A, Scheltema RA, Zheng L, Watson DG, Dujardin JC, Breitling R, Coombs GH, Decuypere S (2010) Towards an unbiased metabolic profiling of protozoan parasites: optimisation of a Leishmania sampling protocol for HILIC-orbitrap analysis. Anal Bioanal Chem 398(5):2059–2069

    Article  Google Scholar 

  67. Krauth-Siegel RL, Bauer H, Schirmer RH (2005) Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia. Angew Chem Int Ed Engl 44(5):690–715

    Article  CAS  Google Scholar 

  68. Fyfe PK, Westrop GD, Silva AM, Coombs GH, Hunter WN (2012) Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation. Proc Natl Acad Sci U S A 109(29):11693–11698

    Article  CAS  Google Scholar 

  69. 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(38):39925–39932

    Article  CAS  Google Scholar 

  70. Darlyuk I, Goldman A, Roberts SC, Ullman B, Rentsch D, Zilberstein D (2009) Arginine homeostasis and transport in the human pathogen Leishmania donovani. J Biol Chem 284(30):19800–19807

    Article  CAS  Google Scholar 

  71. Castilho-Martins EA, Laranjeira da Silva MF, dos Santos MG, Muxel SM, Floeter-Winter LM (2011) Axenic Leishmania amazonensis promastigotes sense both the external and internal arginine pool distinctly regulating the two transporter-coding genes. PLoS One 6(11):e27818

    Article  CAS  Google Scholar 

  72. Basu NK, Kole L, Ghosh A, Das PK (1997) Isolation of a nitric oxide synthase from the protozoan parasite, Leishmania donovani. FEMS Microbiol Lett 156(1):43–47

    Article  CAS  Google Scholar 

  73. Genestra M, de Souza WJ, Cysne-Finkelstein L, Leon LL (2003) Comparative analysis of the nitric oxide production by Leishmania sp. Med Microbiol Immunol 192(4):217–223

    CAS  Google Scholar 

  74. Saunders EC, Ng WW, Chambers JM, Ng M, Naderer T, Krömer JO, Likic VA, McConville MJ (2011) Isotopomer profiling of Leishmania mexicana promastigotes reveals important roles for succinate fermentation and aspartate uptake in tricarboxylic acid cycle (TCA) anaplerosis, glutamate synthesis, and growth. J Biol Chem 286(31):27706–27717

    Article  CAS  Google Scholar 

  75. Inbar E, Canepa GE, Carrillo C, Glaser F, Suter Grotemeyer M, Rentsch D, Zilberstein D, Pereira CA (2012) Lysine transporters in human trypanosomatid pathogens. Amino Acids 42(1):347–360

    Article  CAS  Google Scholar 

  76. Simon MW, Mukkada AJ (1977) Leishmania tropica: regulation and specificity of the methionine transport system in promastigotes. Exp Parasitol 42(1):97–105

    Article  CAS  Google Scholar 

  77. Paes LS, Galvez Rojas RL, Daliry A, Floeter-Winter LM, Ramirez MI, Silber AM (2008) Active transport of glutamate in Leishmania (Leishmania) amazonensis. J Eukaryot Microbiol 55(5):382–387

    Article  CAS  Google Scholar 

  78. Michels PA, Bringaud F, Herman M, Hannaert V (2006) Metabolic functions of glycosomes in trypanosomatids. Biochim Biophys Acta 1763(12):1463–1477

    Article  CAS  Google Scholar 

  79. Ginger ML, Chance ML, Sadler IH, Goad LJ (2001) The biosynthetic incorporation of the intact leucine skeleton into sterol by the trypanosomatid Leishmania mexicana. J Biol Chem 276(15):11674–11682

    Article  CAS  Google Scholar 

  80. Alloatti A, Uttaro AD (2011) Highly specific methyl-end fatty-acid desaturases of trypanosomatids. Mol Biochem Parasitol 175(2):126–132

    Article  CAS  Google Scholar 

  81. Inbar E, Schlisselberg D, Suter Grotemeyer M, Rentsch D, Zilberstein D (2013) A versatile proline/alanine transporter in the unicellular pathogen Leishmania donovani regulates amino acid homoeostasis and osmotic stress responses. Biochem J 449(2):555–566

    Article  CAS  Google Scholar 

  82. Weingärtner A, Drobot B, Herrmann A, Sánchez-Cañete MP, Gamarro F, Castanys S, Günther Pomorski T (2010) Disruption of the lipid-transporting LdMT-LdRos3 complex in Leishmania donovani affects membrane lipid asymmetry but not host cell invasion. PLoS One 5(8):e12443

    Article  Google Scholar 

  83. Naderer T, McConville MJ (2011) Intracellular growth and pathogenesis of Leishmania parasites. Essays Biochem 51:81–95

    CAS  Google Scholar 

  84. Haas A (2007) The phagosome: compartment with a license to kill. Traffic 8(4):311–330

    Article  CAS  Google Scholar 

  85. Verma S, Mehta A, Shaha C (2011) CYP5122A1, a novel cytochrome P450 is essential for survival of Leishmania donovani. PLoS One 6(9):e25273

    Article  CAS  Google Scholar 

  86. Reguera RM, Balaña-Fouce R, Showalter M, Hickerson S, Beverley SM (2009) Leishmania major lacking arginase (ARG) are auxotrophic for polyamines but retain infectivity to susceptible BALB/c mice. Mol Biochem Parasitol 165(1):48–56

    Article  CAS  Google Scholar 

  87. Rosenzweig D, Smith D, Opperdoes F, Stern S, Olafson RW, Zilberstein D (2008) Retooling Leishmania metabolism: from sand fly gut to human macrophage. FASEB J 22(2):590–602

    Article  CAS  Google Scholar 

  88. Saunders EC, DE Souza DP, Naderer T, Sernee MF, Ralton JE, Doyle MA, Macrae JI, Chambers JL, Heng J, Nahid A, Likic VA, McConville MJ (2010) Central carbon metabolism of Leishmania parasites. Parasitology 137(9):1303–1313

    Article  Google Scholar 

  89. Chen M, Zhai L, Christensen SB, Theander TG, Kharazmi A (2001) Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones. Antimicrob Agents Chemother 45(7):2023–2029

    Article  CAS  Google Scholar 

  90. Carvalho L, Luque-Ortega JR, López-Martín C, Castanys S, Rivas L, Gamarro F (2011) The 8-aminoquinoline analogue sitamaquine causes oxidative stress in Leishmania donovani promastigotes by targeting succinate dehydrogenase. Antimicrob Agents Chemother 55(9):4204–4421

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Spanish Ministry of Science and Innovation (MICINN CTQ2011-23562) (CB), FIS PS09-01928 and PI12-02706, (LR) EADS-CASA and Brazilian Air Force (FAB). (CB) L.R. belongs to the Red de Investigación Cooperativa en Enfermedades Tropicales (RICET) RD 06/0021/0006 and RD12/0018/0007. G. A. B. C. is thankful to FAPESP for a doctoral fellowship.

Author information

Authors and Affiliations

  1. Centro de Metabolómica y Bioanálisis (CEMBIO), Unidad Metabolómica, Interacciones y Bioanálisis (UMIB), Facultad de Farmacia, Universidad CEU San Pablo, Campus Monteprincipe, Boadilla del Monte, 28668, Madrid, Spain

    Gisele A. B. Canuto, Emerson A. Castilho-Martins, Coral Barbas & Ángeles López-Gonzálvez

  2. Institute of Chemistry, University of São Paulo (USP), Campus São Paulo. São Paulo, 05508-000, São Paulo, Brazil

    Gisele A. B. Canuto & Marina F. M. Tavares

  3. Collegiate of Medicine, Federal University of Amapá, 68903-419, Macapá, Brazil

    Emerson A. Castilho-Martins

  4. Centro de Investigaciones Biológicas (CSIC), Unidad Metabolómica, Interacciones y Bioanálisis (UMIB), Ramiro de Maeztu 9, 28040, Madrid, Spain

    Luis Rivas

Authors
  1. Gisele A. B. Canuto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emerson A. Castilho-Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marina F. M. Tavares
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis Rivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Coral Barbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ángeles López-Gonzálvez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Luis Rivas or Ángeles López-Gonzálvez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Canuto, G.A.B., Castilho-Martins, E.A., Tavares, M.F.M. et al. Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania . Anal Bioanal Chem 406, 3459–3476 (2014). https://doi.org/10.1007/s00216-014-7772-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-014-7772-1

Keywords

Search

Navigation