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The potential of metabolomics for Leishmania research in the post-genomics era

Published online by Cambridge University Press:  29 January 2010

RICHARD A. SCHELTEMA ,
SASKIA DECUYPERE ,
RUBEN T'KINDT ,
JEAN-CLAUDE DUJARDIN ,
GRAHAM H. COOMBS  and
RAINER BREITLING
RICHARD A. SCHELTEMA
Affiliation:
Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands
SASKIA DECUYPERE
Affiliation:
Department of Parasitology, Unit of Molecular Parasitology, Institute of Tropical Medicine, Antwerp B-2000, Belgium Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, Scotland
RUBEN T'KINDT
Affiliation:
Department of Parasitology, Unit of Molecular Parasitology, Institute of Tropical Medicine, Antwerp B-2000, Belgium Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, Scotland
JEAN-CLAUDE DUJARDIN
Affiliation:
Department of Parasitology, Unit of Molecular Parasitology, Institute of Tropical Medicine, Antwerp B-2000, Belgium
GRAHAM H. COOMBS
Affiliation:
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, Scotland
RAINER BREITLING*
Affiliation:
Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands
*
*Address correspondence to: Rainer Breitling (r.breitling@rug.nl), Tel: +31-50-3638088, Fax: +31-50-3637976.
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Summary

The post-genomics era has provided researchers with access to a new generation of tools for the global characterization and understanding of pathogen diversity. This review provides a critical summary of published Leishmania post-genomic research efforts to date, and discusses the potential impact of the addition of metabolomics to the post-genomic toolbox. Metabolomics aims at understanding biology by comprehensive metabolite profiling. We present an overview of the design and interpretation of metabolomics experiments in the context of Leishmania research. Sample preparation, measurement techniques, and bioinformatics analysis of the generated complex datasets are discussed in detail. To illustrate the concepts and the expected results of metabolomics analyses, we also present an overview of comparative metabolic profiles of drug-sensitive and drug-resistant Leishmania donovani clinical isolates.

Keywords

Post-genomics researchmetabolomicsmass spectrometryliquid chromatographyLeishmania
Type
Research Article
Information
Parasitology , Volume 137 , Special Issue 9: Insights into the metabolomes of parasites , August 2010 , pp. 1291 - 1302
Copyright
Copyright © Cambridge University Press 2010

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References

REFERENCES

Atherton, H. J., Bailey, N. J., Zhang, W., Taylor, J., Major, H., Shockcor, J., Clarke, K. and Griffin, J. L. (2006). A combined 1H-NMR spectroscopy- and mass spectrometry-based metabolomic study of the PPAR-alpha null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome. Physiological Genomics 27, 178–186. doi: 10.1152/physiolgenomics.00060.2006.CrossRefGoogle ScholarPubMed
Baxevanis, A. D., Page, R. D., Petsko, G. A., Stein, L. D. and Stormo, G. D. (2002). Current Protocols in Bioinformatics. John Wiley & Sons, Inc., Hoboken, NJ, USA.Google Scholar
Bente, M., Harder, S., Wiesgigl, M., Heukeshoven, J., Gelhaus, C., Krause, E., Clos, J. and Bruchhaus, I. (2003). Developmentally induced changes of the proteome in the protozoan parasite Leishmania donovani. Proteomics 3, 1811–1829. doi: 10.1002/pmic.200300462.CrossRefGoogle ScholarPubMed
Bocker, S. and Rasche, F. (2008). Towards de novo identification of metabolites by analyzing tandem mass spectra. Bioinformatics 24, i49–55. doi: 10.1093/bioinformatics/btn270.CrossRefGoogle ScholarPubMed
Breitling, R., Ritchie, S., Goodenowe, D., Stewart, M. L. and Barrett, M. P. (2006). Ab initio prediction of metabolic networks using Fourier transform mass spectrometry data. Metabolomics 2, 155–164. doi: 10.1007/s11306-006-0029-z.CrossRefGoogle ScholarPubMed
Breitling, R., Vitkup, D. and Barrett, M. P. (2008). New surveyor tools for charting microbial metabolic maps. Nature Reviews, Microbiology 6, 156–161. doi: 10.1038/nrmicro1797.CrossRefGoogle ScholarPubMed
Brobey, R. K. B., Mei, F. C., Cheng, X. and Soong, L. (2006). Comparative two-dimensional gel electrophoresis maps for promastigotes of Leishmania amazonensis and Leishmania major. Brazilian Journal of Infectious Diseases: An Official Publication of the Brazilian Society of Infectious Diseases 10, 1–6. doi: /S1413-86702006000100001.CrossRefGoogle ScholarPubMed
Chavali, A. K., Whittemore, J. D., Eddy, J. A., Williams, K. T. and Papin, J. A. (2008). Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major. Molecular Systems Biology 4, 177. doi: 10.1038/msb.2008.15.CrossRefGoogle ScholarPubMed
Clayton, C. and Shapira, M. (2007). Post-transcriptional regulation of gene expression in trypanosomes and leishmanias. Molecular and Biochemical Parasitology 156, 93–101. doi: 10.1016/j.molbiopara.2007.07.007.CrossRefGoogle ScholarPubMed
Cohen-Freue, G., Holzer, T. R., Forney, J. D. and McMaster, W. R. (2007). Global gene expression in Leishmania. International Journal for Parasitology 37, 1077–1086. doi: 10.1016/j.ijpara.2007.04.011.CrossRefGoogle ScholarPubMed
De Souza, D. P., Saunders, E. C., McConville, M. J. and Likic, V. A. (2006). Progressive peak clustering in GC-MS Metabolomic experiments applied to Leishmania parasites. Bioinformatics 22, 1391–1396. doi: 10.1093/bioinformatics/btl085.CrossRefGoogle ScholarPubMed
Doyle, M., MacRae, J., De Souza, D., Saunders, E., McConville, M. and Likic, V. (2009). LeishCyc: a biochemical pathways database for Leishmania major. BMC Systems Biology 3, 57. doi: 10.1186/1752-0509-3-57.CrossRefGoogle ScholarPubMed
Drummelsmith, J., Brochu, V., Girard, I., Messier, N. and Ouellette, M. (2003). Proteome mapping of the protozoan parasite Leishmania and application to the study of drug targets and resistance mechanisms. Molecular and Cellular Proteomics 2, 146–155. doi: 10.1074/mcp.M200085-MCP200.CrossRefGoogle Scholar
Drummelsmith, J., Girard, I., Trudel, N. and Ouellette, M. (2004). Differential protein expression analysis of Leishmania major reveals novel roles for methionine adenosyltransferase and S-adenosylmethionine in methotrexate resistance. Journal of Biological Chemistry 279, 33273–33280. doi: 10.1074/jbc.M405183200.CrossRefGoogle ScholarPubMed
Dujardin, J. (2009). Structure, dynamics and function of Leishmania genome: resolving the puzzle of infection, genetics and evolution? Infection, Genetics and Evolution: Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases 9, 290–297. doi: 10.1016/j.meegid.2008.11.007.CrossRefGoogle ScholarPubMed
Dunn, W. B., Bailey, N. J. C. and Johnson, H. E. (2005). Measuring the metabolome: current analytical technologies. The Analyst 130, 606–625.CrossRefGoogle ScholarPubMed
Dunn, W. B., Broadhurst, D., Brown, M., Baker, P. N., Redman, C. W. G., Kenny, L. C. and Kell, D. B. (2008). Metabolic profiling of serum using Ultra Performance Liquid Chromatography and the LTQ-Orbitrap mass spectrometry system. Journal of Chromatography B 871, 288–298. doi: 10.1016/j.jchromb.2008.03.021.CrossRefGoogle ScholarPubMed
Fadili, K. E., Drummelsmith, J., Roy, G., Jardim, A. and Ouellette, M. (2009). Down regulation of KMP-11 in Leishmania infantum axenic antimony resistant amastigotes as revealed by a proteomic screen. Experimental Parasitology 123, 51–57. doi: 10.1016/j.exppara.2009.05.013.CrossRefGoogle ScholarPubMed
Fahy, E., Sud, M., Cotter, D. and Subramaniam, S. (2007). LIPID MAPS online tools for lipid research. Nucleic Acids Research 35(Web Server issue), W606–612. doi: 10.1093/nar/gkm324.CrossRefGoogle ScholarPubMed
Faijes, M., Mars, A. and Smid, E. (2007). Comparison of quenching and extraction methodologies for metabolome analysis of Lactobacillus plantarum. Microbial Cell Factories 6, 27. doi: 10.1186/1475-2859-6-27.CrossRefGoogle ScholarPubMed
Fernie, A. R., Trethewey, R. N., Krotzky, A. J. and Willmitzer, L. (2004). Metabolite profiling: from diagnostics to systems biology. Nature Reviews Molecular Cell Biology 5, 763–769. doi: 10.1038/nrm1451.CrossRefGoogle ScholarPubMed
Fiehn, O. (2001). Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comparative and Functional Genomics 2, 155–168. doi: 10.1002/cfg.82.CrossRefGoogle ScholarPubMed
Gibellini, F., Hunter, W. N. and Smith, T. K. (2009). The ethanolamine branch of the Kennedy pathway is essential in the bloodstream form of Trypanosoma brucei. Molecular Microbiology 73, 826–843. doi: 10.1111/j.1365-2958.2009.06764.x.CrossRefGoogle ScholarPubMed
Goodacre, R., Vaidyanathan, S., Dunn, W. B., Harrigan, G. G. and Kell, D. B. (2004). Metabolomics by numbers: acquiring and understanding global metabolite data. Trends in Biotechnology 22, 245–252. doi: 10.1016/j.tibtech.2004.03.007.CrossRefGoogle ScholarPubMed
Guerbouj, S., Victoir, K., Guizani, I., Seridi, N., Nuwayri-Salti, N., Belkaid, M., Ismail, R. B., Le Ray, D. and Dujardin, J. C. (2001). Gp63 gene polymorphism and population structure of Leishmania donovani complex: influence of the host selection pressure? Parasitology 122, 25–35.Google Scholar
Guimond, C., Trudel, N., Brochu, C., Marquis, N., Fadili, A. E., Peytavi, R., Briand, G., Richard, D., Messier, N., Papadopoulou, B., Corbeil, J., Bergeron, M. G., Legare, D. and Ouellette, M. (2003). Modulation of gene expression in Leishmania drug resistant mutants as determined by targeted DNA microarrays. Nucleic Acids Research 31, 5886–5896. doi: 10.1093/nar/gkg806.CrossRefGoogle ScholarPubMed
Hall, N. (2007). Advanced sequencing technologies and their wider impact in microbiology. Journal of Experimental Biology 210, 1518–1525. doi: 10.1242/jeb.001370.CrossRefGoogle ScholarPubMed
Han, J., Danell, R., Patel, J., Gumerov, D., Scarlett, C., Speir, J., Parker, C., Rusyn, I., Zeisel, S. and Borchers, C. (2008). Towards high-throughput metabolomics using ultrahigh-field Fourier transform ion cyclotron resonance mass spectrometry. Metabolomics 4, 128–140. doi: 10.1007/s11306-008-0104-8.CrossRefGoogle ScholarPubMed
Hardman, M. and Makarov, A. A. (2003). Interfacing the orbitrap mass analyzer to an electrospray ion source. Analytical Chemistry 75, 1699–1705.CrossRefGoogle Scholar
Holzer, T. R., McMaster, W. and Forney, J. D. (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. Molecular and Biochemical Parasitology 146, 198–218. doi: 10.1016/j.molbiopara.2005.12.009.CrossRefGoogle ScholarPubMed
Inga, R., Doncker, S. D., Gomez, J., Lopez, M., Garcia, R., Ray, D. L., Arevalo, J. and Dujardin, J. (1998). Relation between variation in copy number of ribosomal RNA encoding genes and size of harbouring chromosomes in Leishmania of subgenus Viannia. Molecular and Biochemical Parasitology 92, 219–228. doi: 10.1016/S0166-6851(98)00009-7.CrossRefGoogle ScholarPubMed
Ivens, A. C., Peacock, C. S., Worthey, E. A., Murphy, L., Aggarwal, G., Berriman, M., Sisk, E., Rajandream, M., Adlem, E., Aert, R., Anupama, A., Apostolou, Z., Attipoe, P., Bason, N., Bauser, C., Beck, A., Beverley, S. M., Bianchettin, G., Borzym, K., Bothe, G., Bruschi, C. V., Collins, M., Cadag, E., Ciarloni, L., Clayton, C., Coulson, R. M. R., Cronin, A., Cruz, A. K., Davies, R. M., De Gaudenzi, J., Dobson, D. E., Duesterhoeft, A., Fazelina, G., Fosker, N., Frasch, A. C., Fraser, A., Fuchs, M., Gabel, C., Goble, A., Goffeau, A., Harris, D., Hertz-Fowler, C., Hilbert, H., Horn, D., Huang, Y., Klages, S., Knights, A., Kube, M., Larke, N., Litvin, L., Lord, A., Louie, T., Marra, M., Masuy, D., Matthews, K., Michaeli, S., Mottram, J. C., Müller-Auer, S., Munden, H., Nelson, S., Norbertczak, H., Oliver, K., O'Neil, S., Pentony, M., Pohl, T. M., Price, C., Purnelle, B., Quail, M. A., Rabbinowitsch, E., Reinhardt, R., Rieger, M., Rinta, J., Robben, J., Robertson, L., Ruiz, J. C., Rutter, S., Saunders, D., Schäfer, M., Schein, J., Schwartz, D. C., Seeger, K., Seyler, A., Sharp, S., Shin, H., Sivam, D., Squares, R., Squares, S., Tosato, V., Vogt, C., Volckaert, G., Wambutt, R., Warren, T., Wedler, H., Woodward, J., Zhou, S., Zimmermann, W., Smith, D. F., Blackwell, J. M., Stuart, K. D., Barrell, B. and Myler, P. J. (2005). The genome of the kinetoplastid parasite, Leishmania major. Science 309, 436–442. doi: 10.1126/science.1112680.CrossRefGoogle ScholarPubMed
Kamleh, A., Barrett, M. P., Wildridge, D., Burchmore, R. J. S., Scheltema, R. A. and Watson, D. G. (2008). Metabolomic profiling using Orbitrap Fourier transform mass spectrometry with hydrophilic interaction chromatography: a method with wide applicability to analysis of biomolecules. Rapid Communications in Mass Spectrometry 22, 1912–1918. doi: 10.1002/rcm.3564.CrossRefGoogle ScholarPubMed
Kanehisa, M., Goto, S., Kawashima, S. and Nakaya, A. (2002). The KEGG databases at GenomeNet. Nucleic Acids Research 30, 42–46.CrossRefGoogle ScholarPubMed
Kell, D. and Westerhoff, H. (1986). Metabolic control theory: its role in microbiology and biotechnology. FEMS Microbiology Letters 39, 305–320. doi: 10.1111/j.1574-6968.1986.tb01863.x.CrossRefGoogle Scholar
Kell, D. B. (2004). Metabolomics and systems biology: making sense of the soup. Current Opinion in Microbiology 7, 296–307. doi: 10.1016/j.mib.2004.04.012.CrossRefGoogle ScholarPubMed
Keller, B. O., Sui, J., Young, A. B. and Whittal, R. M. (2008). Interferences and contaminants encountered in modern mass spectrometry. Analytica Chimica Acta 627, 71–81. doi: 10.1016/j.aca.2008.04.043.CrossRefGoogle ScholarPubMed
Leifso, K., Cohen-Freue, G., Dogra, N., Murray, A. and McMaster, W. R. (2007). Genomic and proteomic expression analysis of Leishmania promastigote and amastigote life stages: The Leishmania genome is constitutively expressed. Molecular and Biochemical Parasitology 152, 35–46. doi: 10.1016/j.molbiopara.2006.11.009.Google Scholar
Leprohon, P., Legare, D., Raymond, F., Madore, E., Hardiman, G., Corbeil, J. and Ouellette, M. (2009). Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum. Nucleic Acids Research 37, 1387–1399. doi: 10.1093/nar/gkn1069.Google Scholar
Lu, X., Zhao, X., Bai, C., Zhao, C., Lu, G. and Xu, G. (2008). LC-MS-based metabonomics analysis. Journal of Chromatography B 866, 64–76. doi: 10.1016/j.jchromb.2007.10.022.CrossRefGoogle ScholarPubMed
McConville, M. J., de Souza, D., Saunders, E., Likic, V. A. and Naderer, T. (2007). Living in a phagolysosome; metabolism of Leishmania amastigotes. Trends in Parasitology 23, 368–375. doi: 10.1016/j.pt.2007.06.009.CrossRefGoogle Scholar
McDonagh, P. D., Myler, P. J. and Stuart, K. (2000). The unusual gene organization of Leishmania major chromosome 1 may reflect novel transcription processes. Nucleic Acids Research 28, 2800–2803. doi: 10.1093/nar/28.14.2800.Google Scholar
McNicoll, F., Drummelsmith, J., Müller, M., Madore, É., Boilard, N., Ouellette, M. and Papadopoulou, B. (2006). A combined proteomic and transcriptomic approach to the study of stage differentiation in Leishmania infantum. Proteomics 6, 3567–3581. doi: 10.1002/pmic.200500853.CrossRefGoogle Scholar
Morozova, O. and Marra, M. A. (2008). Applications of next-generation sequencing technologies in functional genomics. Genomics 92, 255–264. doi: 10.1016/j.ygeno.2008.07.001.CrossRefGoogle ScholarPubMed
Ouellette, M., Ubeda, J., Leprohon, P., Mukherjee, A., Brotherton, C., Moreira, W., Coelho, A. and Raymond, F. (2009). Whole genome analysis of drug resistance in Leishmania. In Abstracts World Conference Leishmaniasis 4.Google Scholar
Pasikanti, K. K., Ho, P. and Chan, E. (2008). Gas chromatography/mass spectrometry in metabolic profiling of biological fluids. Journal of Chromatography B 871, 202–211. doi: 10.1016/j.jchromb.2008.04.033.Google Scholar
Peacock, C. S., Seeger, K., Harris, D., Murphy, L., Ruiz, J. C., Quail, M. A., Peters, N., Adlem, E., Tivey, A., Aslett, M., Kerhornou, A., Ivens, A., Fraser, A., Rajandream, M., Carver, T., Norbertczak, H., Chillingworth, T., Hance, Z., Jagels, K., Moule, S., Ormond, D., Rutter, S., Squares, R., Whitehead, S., Rabbinowitsch, E., Arrowsmith, C., White, B., Thurston, S., Bringaud, F., Baldauf, S. L., Faulconbridge, A., Jeffares, D., Depledge, D. P., Oyola, S. O., Hilley, J. D., Brito, L. O., Tosi, L. R. O., Barrell, B., Cruz, A. K., Mottram, J. C., Smith, D. F. and Berriman, M. (2007). Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nature Genetics 39, 839–847. doi: 10.1038/ng2053.CrossRefGoogle ScholarPubMed
Rochette, A., Raymond, F., Ubeda, J., Smith, M., Messier, N., Boisvert, S., Rigault, P., Corbeil, J., Ouellette, M. and Papadopoulou, B. (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. doi: 10.1186/1471-2164-9-255.CrossRefGoogle ScholarPubMed
Rogers, S., Scheltema, R. A., Girolami, M. and Breitling, R. (2009). Probabilistic assignment of formulas to mass peaks in metabolomics experiments. Bioinformatics 25, 512–518. doi: 10.1093/bioinformatics/btn642.CrossRefGoogle ScholarPubMed
Rosenzweig, D., Smith, D., Opperdoes, F., Stern, S., Olafson, R. W. and Zilberstein, D. (2008). Retooling Leishmania metabolism: from sand fly gut to human macrophage. FASEB Journal 22, 590–602. doi: 10.1096/fj.07-9254com.CrossRefGoogle ScholarPubMed
Salotra, P., Duncan, R. C., Singh, R., Raju, B. S., Sreenivas, G. and Nakhasi, H. L. (2006). Upregulation of surface proteins in Leishmania donovani isolated from patients of post kala-azar dermal leishmaniasis. Microbes and Infection 8, 637–644. doi: 10.1016/j.micinf.2005.08.018.CrossRefGoogle ScholarPubMed
Saxena, A., Lahav, T., Holl, N., Aggarwal, G., Anupama, A., Huang, Y., Volpin, H., Myler, P. and Zilberstein, D. (2007). Analysis of the Leishmania donovani transcriptome reveals an ordered progression of transient and permanent changes in gene expression during differentiation. Molecular and Biochemical Parasitology 152, 53–65. doi: 10.1016/j.molbiopara.2006.11.011.CrossRefGoogle ScholarPubMed
Sellick, C. A., Hansen, R., Maqsood, A. R., Dunn, W. B., Stephens, G. M., Goodacre, R. and Dickson, A. J. (2009). Effective quenching processes for physiologically valid metabolite profiling of suspension cultured mammalian cells. Analytical Chemistry 81, 174–183. doi: 10.1021/ac8016899.Google Scholar
Sharma, S., Singh, G., Chavan, H. D. and Dey, C. S. (2003). Proteomic analysis of wild type and arsenite-resistant Leishmania donovani. Experimental Parasitology 123, 369–376. doi: 10.1016/j.exppara.2009.08.003.CrossRefGoogle Scholar
Singh, G., Chavan, H. D. and Dey, C. S. (2008). Proteomic analysis of miltefosine-resistant Leishmania reveals the possible involvement of eukaryotic initiation factor 4A (eIF4A). International Journal of Antimicrobial Agents 31, 584–586. doi: 10.1016/j.ijantimicag.2008.01.032.Google Scholar
Singh, N., Almeida, R., Kothari, H., Kumar, P., Mandal, G., Chatterjee, M., Venkatachalam, S., Govind, M. K., Mandal, S. K. and Sundar, S. (2007). Differential gene expression analysis in antimony-unresponsive Indian kala azar (visceral leishmaniasis) clinical isolates by DNA microarray. Parasitology 134, 777–787. doi: 10.1017/S0031182007002284.CrossRefGoogle ScholarPubMed
Smith, C. A., O'Maille, G., Want, E. J., Qin, C., Trauger, S. A., Brandon, T. R., Custodio, D. E., Abagyan, R. and Siuzdak, G. (2005). METLIN: a metabolite mass spectral database. Therapeutic Drug Monitoring 27, 747–751.CrossRefGoogle Scholar
Smith, D. F., Peacock, C. S. and Cruz, A. K. (2007). Comparative genomics: from genotype to disease phenotype in the leishmaniases. International Journal for Parasitology 37, 1173–1186. doi: 10.1016/j.ijpara.2007.05.015.CrossRefGoogle ScholarPubMed
Srividya, G., Duncan, R., Sharma, P., Raju, B. V. S., Nakhasi, H. L. and Salotra, P. (2007). Transcriptome analysis during the process of in vitro differentiation of Leishmania donovani using genomic microarrays. Parasitology 134, 1527–1539. doi: 10.1017/S003118200700296X.CrossRefGoogle ScholarPubMed
Sturm, N. R., Martinez, L. I. T. and Thomas, S. (2008). Kinetoplastid genomics: The thin end of the wedge. Infection, Genetics and Evolution 8, 901–906. doi: 10.1016/j.meegid.2008.07.001.Google Scholar
Tautenhahn, R., Böttcher, C. and Neumann, S. (2007). Annotation of LC/ESI-MS Mass Signals. In Bioinformatics Research and Development. (ed. Hochreiter, S. and Wagner, R.), pp. 371–380. Springer-Verlag, Heidelberg, Germany.CrossRefGoogle Scholar
Ubeda, J., Legare, D., Raymond, F., Ouameur, A., Boisvert, S., Rigault, P., Corbeil, J., Tremblay, M., Olivier, M., Papadopoulou, B. and Ouellette, M. (2008). Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biology 9, R115. doi: 10.1186/gb-2008-9-7-r115.Google Scholar
van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L. and Hankemeier, T. (2007). Microbial metabolomics: toward a platform with full metabolome coverage. Analytical Biochemistry 370, 17–25. doi: 10.1016/j.ab.2007.07.022.Google Scholar
Vergnes, B., Gourbal, B., Girard, I., Sundar, S., Drummelsmith, J. and 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. Molecular and Cellular Proteomics 6, 88–101. doi: 10.1074/mcp.M600319-MCP200.Google Scholar
Victoir, K., Dujardin, J. C., de Doncker, S., Barker, D. C., Arevalo, J., Hamers, R. and Le Ray, D. (1995). Plasticity of gp63 gene organization in Leishmania (Viannia) braziliensis and Leishmania (Viannia) peruviana. Parasitology 111, 265–273.CrossRefGoogle ScholarPubMed
Villas-Bôas, S. G. and Bruheim, P. (2007). Cold glycerol-saline: The promising quenching solution for accurate intracellular metabolite analysis of microbial cells. Analytical Biochemistry 370, 87–97. doi: 10.1016/j.ab.2007.06.028.CrossRefGoogle ScholarPubMed
Wang, Y., Xiao, J., Suzek, T. O., Zhang, J., Wang, J. and Bryant, S. H. (2009). PubChem: a public information system for analyzing bioactivities of small molecules. Nucleic Acids Research 37, W623–633. doi: 10.1093/nar/gkp456.CrossRefGoogle ScholarPubMed
Winder, C. L., Dunn, W. B., Schuler, S., Broadhurst, D., Jarvis, R., Stephens, G. M. and Goodacre, R. (2008). Global metabolic profiling of Escherichia coli cultures: an evaluation of methods for quenching and extraction of intracellular metabolites. Analytical Chemistry 80, 2939–2948. doi: 10.1021/ac7023409.Google Scholar
Wishart, D. S., Tzur, D., Knox, C., Eisner, R., Guo, A. C., Young, N., Cheng, D., Jewell, K., Arndt, D., Sawhney, S., Fung, C., Nikolai, L., Lewis, M., Coutouly, M., Forsythe, I., Tang, P., Shrivastava, S., Jeroncic, K., Stothard, P., Amegbey, G., Block, D., Hau, D. D., Wagner, J., Miniaci, J., Clements, M., Gebremedhin, M., Guo, N., Zhang, Y., Duggan, G. E., MacInnis, G. D., Weljie, A. M., Dowlatabadi, R., Bamforth, F., Clive, D., Greiner, R., Li, L., Marrie, T., Sykes, B. D., Vogel, H. J. and Querengesser, L. (2007). HMDB: the human metabolome database. Nucleic Acids Research 35 (Database issue), D521–526. doi: 10.1093/nar/gkl923.CrossRefGoogle ScholarPubMed
Wittmann, C., Krömer, J. O., Kiefer, P., Binz, T. and Heinzle, E. (2004). Impact of the cold shock phenomenon on quantification of intracellular metabolites in bacteria. Analytical Biochemistry 327, 135–139. doi: 10.1016/j.ab.2004.01.002.CrossRefGoogle ScholarPubMed