Determination of antiprotozoal drug mechanisms by metabolomics approaches

SUMMARY The discovery, development and optimal utilization of pharmaceuticals can be greatly enhanced by knowledge of their modes of action. However, many drugs currently on the market act by unknown mechanisms. Untargeted metabolomics offers the potential to discover modes of action for drugs that perturb cellular metabolism. Development of high resolution LC-MS methods and improved data analysis software now allows rapid detection of drug-induced changes to cellular metabolism in an untargeted manner. Several studies have demonstrated the ability of untargeted metabolomics to provide unbiased target discovery for antimicrobial drugs, in particular for antiprotozoal agents. Furthermore, the utilization of targeted metabolomics techniques has enabled validation of existing hypotheses regarding antiprotozoal drug mechanisms. Metabolomics approaches are likely to assist with optimization of new drug candidates by identification of drug targets, and by allowing detailed characterization of modes of action and resistance of existing and novel antiprotozoal drugs.

[1]  大房 健.  基礎講座 電気泳動(Electrophoresis) , 2005 .

[2]  M. Phillips.  Stoking the drug target pipeline for human African trypanosomiasis , 2012, Molecular microbiology.

[3]  C. Barbas,et al.  CE‐ESI‐MS metabolic fingerprinting of Leishmania resistance to antimony treatment , 2012, Electrophoresis.

[4]  Simon Rogers,et al.  Probabilistic assignment of formulas to mass peaks in metabolomics experiments , 2009, Bioinform..

[5]  Oliver Fiehn,et al.  Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research , 2009, Metabolomics.

[6]  James R. Brown,et al.  Thousands of chemical starting points for antimalarial lead identification , 2010, Nature.

[7]  Peer Bork,et al.  iPath2.0: interactive pathway explorer , 2011, Nucleic Acids Res..

[8]  M. Barrett,et al.  Human African trypanosomiasis: pharmacological re‐engagement with a neglected disease , 2007, British journal of pharmacology.

[9]  Rainer Breitling,et al.  IDEOM: an Excel interface for analysis of LC-MS-based metabolomics data , 2012, Bioinform..

[10]  S. Neumann,et al.  CAMERA: an integrated strategy for compound spectra extraction and annotation of liquid chromatography/mass spectrometry data sets. , 2012, Analytical chemistry.

[11]  Michael J. Keiser,et al.  The Chemical Basis of Pharmacology , 2010, Biochemistry.

[12]  R. Breitling,et al.  The potential of metabolomics for Leishmania research in the post-genomics era , 2010, Parasitology.

[13]  N. White.  Counter Perspective: Artemisinin Resistance: Facts, Fears, and Fables , 2012, The American journal of tropical medicine and hygiene.

[14]  R. Breitling,et al.  Toward global metabolomics analysis with hydrophilic interaction liquid chromatography-mass spectrometry: improved metabolite identification by retention time prediction. , 2011, Analytical chemistry.

[15]  R. Breitling,et al.  Towards an unbiased metabolic profiling of protozoan parasites: optimisation of a Leishmania sampling protocol for HILIC-orbitrap analysis , 2010, Analytical and bioanalytical chemistry.

[16]  Arjen Lommen,et al.  MetAlign: interface-driven, versatile metabolomics tool for hyphenated full-scan mass spectrometry data preprocessing. , 2009, Analytical chemistry.

[17]  Nisha Singh,et al.  Leishmaniasis: current status of available drugs and new potential drug targets. , 2012, Asian Pacific journal of tropical medicine.

[18]  M. Čuperlović-Culf,et al.  Cell culture metabolomics: applications and future directions. , 2010, Drug discovery today.

[19]  Xin Lu,et al.  Investigation on response of the metabolites in tricarboxylic acid cycle of Escherichi coli and Pseudomonas aeruginosa to antibiotic perturbation by capillary electrophoresis. , 2007, Journal of pharmaceutical and biomedical analysis.

[20]  Shan He,et al.  MaConDa: a publicly accessible mass spectrometry contaminants database , 2012, Bioinform..

[21]  J. Burrows,et al.  The global pipeline of new medicines for the control and elimination of malaria , 2012, Malaria Journal.

[22]  R. Abagyan,et al.  XCMS: processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification. , 2006, Analytical chemistry.

[23]  Adam R Renslo,et al.  Drug discovery and development for neglected parasitic diseases , 2006, Nature chemical biology.

[24]  Stuart L. Schreiber,et al.  Printing Small Molecules as Microarrays and Detecting Protein−Ligand Interactions en Masse , 1999 .

[25]  Ralf J. M. Weber,et al.  Mass appeal: metabolite identification in mass spectrometry-focused untargeted metabolomics , 2012, Metabolomics.

[26]  M. Barrett,et al.  Metabolomic analysis of trypanosomatid protozoa. , 2012, Molecular and biochemical parasitology.

[27]  Yongyuth Yuthavong,et al.  Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target , 2012, Proceedings of the National Academy of Sciences.

[28]  R. Powers,et al.  Predicting the in vivo mechanism of action for drug leads using NMR metabolomics. , 2012, ACS chemical biology.

[29]  R. Pink,et al.  Opportunities and Challenges in Antiparasitic Drug Discovery , 2005, Nature Reviews Drug Discovery.

[30]  Anang A. Shelat,et al.  Chemical genetics of Plasmodium falciparum , 2010, Nature.

[31]  A. Fairlamb,et al.  Chemical and genetic validation of dihydrofolate reductase–thymidylate synthase as a drug target in African trypanosomes , 2008, Molecular microbiology.

[32]  Nigel W. Hardy,et al.  Proposed minimum reporting standards for chemical analysis , 2007, Metabolomics.

[33]  Matej Oresic,et al.  MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data , 2010, BMC Bioinformatics.

[34]  R. Madhubala,et al.  Paromomycin Affects Translation and Vesicle-Mediated Trafficking as Revealed by Proteomics of Paromomycin –Susceptible –Resistant Leishmania donovani , 2011, PloS one.

[35]  Suzanne M. Paley,et al.  The Pathway Tools cellular overview diagram and Omics Viewer , 2006, Nucleic acids research.

[36]  P. Loria,et al.  Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials. , 1999, The Biochemical journal.

[37]  V. Barton,et al.  The Molecular Mechanism of Action of Artemisinin—The Debate Continues , 2010, Molecules.

[38]  K. M. Watts,et al.  A second target of the antimalarial and antibacterial agent fosmidomycin revealed by cellular metabolic profiling. , 2011, Biochemistry.

[39]  B. Hall,et al.  Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites* , 2011, The Journal of Biological Chemistry.

[40]  J. Rabinowitz,et al.  A domino effect in antifolate drug action in Escherichia coli. , 2008, Nature chemical biology.

[41]  T. Wells,et al.  New medicines to improve control and contribute to the eradication of malaria , 2010, Malaria Journal.

[42]  P. Olliaro,et al.  Mode of action and mechanisms of resistance for antimalarial drugs. , 2001, Pharmacology & therapeutics.

[43]  Rainer Breitling,et al.  Separating the wheat from the chaff: a prioritisation pipeline for the analysis of metabolomics datasets , 2011, Metabolomics.

[44]  David P Leader,et al.  Pathos: A web facility that uses metabolic maps to display experimental changes in metabolites identified by mass spectrometry , 2011, Rapid communications in mass spectrometry : RCM.

[45]  Francisco-Javier Gamo,et al.  Global phenotypic screening for antimalarials. , 2012, Chemistry & biology.

[46]  J. Baell,et al.  Identification of Compounds with Anti-Proliferative Activity against Trypanosoma brucei brucei Strain 427 by a Whole Cell Viability Based HTS Campaign , 2012, PLoS neglected tropical diseases.

[47]  J. Hemingway,et al.  Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria , 2012, Proceedings of the National Academy of Sciences.

[48]  P. Alonso,et al.  New medicines to improve control and contribute to the eradication of malaria. , 2009, Nature reviews. Drug discovery.

[49]  E. Want,et al.  Liquid chromatography-mass spectrometry based global metabolite profiling: a review. , 2012, Analytica chimica acta.

[50]  M. McConville,et al.  The Leishmania–macrophage interaction: a metabolic perspective , 2007, Cellular microbiology.

[51]  J. Idle,et al.  Metabolomics and its potential in drug development. , 2013, Biochemical pharmacology.

[52]  H Hirumi,et al.  Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. , 1989, The Journal of parasitology.

[53]  W. Dunn,et al.  Measuring the metabolome: current analytical technologies. , 2005, The Analyst.

[54]  F. Opperdoes,et al.  Ether--lipid (alkyl-phospholipid) metabolism and the mechanism of action of ether--lipid analogues in Leishmania. , 2000, Molecular and biochemical parasitology.

[55]  Xiao-Jiang Feng,et al.  Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy , 2008, Nature Biotechnology.

[56]  V. Avery,et al.  Development and Optimization of a Novel 384-Well Anti-Malarial Imaging Assay Validated for High-Throughput Screening , 2012, The American journal of tropical medicine and hygiene.

[57]  Michael P Barrett,et al.  Development of novel drugs for human African trypanosomiasis. , 2011, Future microbiology.

[58]  Michael P. Barrett,et al.  Management of trypanosomiasis and leishmaniasis , 2012, British medical bulletin.

[59]  R. Breitling,et al.  Metabolomics to Unveil and Understand Phenotypic Diversity between Pathogen Populations , 2010, PLoS neglected tropical diseases.

[60]  N. Grishin,et al.  X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with alpha-difluoromethylornithine. , 1999, Biochemistry.

[61]  M. Barrett,et al.  Evaluation of coupling reversed phase, aqueous normal phase, and hydrophilic interaction liquid chromatography with Orbitrap mass spectrometry for metabolomic studies of human urine. , 2012, Analytical chemistry.

[62]  R. Breitling,et al.  PeakML/mzMatch: a file format, Java library, R library, and tool-chain for mass spectrometry data analysis. , 2011, Analytical chemistry.

[63]  Manuel Llinás,et al.  Co-inhibition of Plasmodium falciparum S-Adenosylmethionine Decarboxylase/Ornithine Decarboxylase Reveals Perturbation-specific Compensatory Mechanisms by Transcriptome, Proteome, and Metabolome Analyses* , 2009, Journal of Biological Chemistry.

[64]  Manuel Liebeke,et al.  Exometabolome Analysis Identifies Pyruvate Dehydrogenase as a Target for the Antibiotic Triphenylbismuthdichloride in Multiresistant Bacterial Pathogens* , 2011, The Journal of Biological Chemistry.

[65]  Eleanor C. Saunders,et al.  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* , 2011, The Journal of Biological Chemistry.

[66]  Beat Ernst,et al.  Drug discovery today. , 2003, Current topics in medicinal chemistry.

[67]  Mark C. Field,et al.  Pyrimidine Salvage in Trypanosoma brucei Bloodstream Forms and the Trypanocidal Action of Halogenated Pyrimidines , 2013, Molecular Pharmacology.

[68]  J. Thomas-Oates,et al.  Metabolomic applications of HILIC-LC-MS. , 2010, Mass spectrometry reviews.

[69]  Laurent Debrauwer,et al.  Use of reconstituted metabolic networks to assist in metabolomic data visualization and mining , 2010, Metabolomics.

[70]  R. Powers,et al.  Use of NMR metabolomics to analyze the targets of D-cycloserine in mycobacteria: role of D-alanine racemase. , 2007, Journal of proteome research.

[71]  F. Nosten,et al.  Artemisinin-based combination treatment of falciparum malaria. , 2007, The American journal of tropical medicine and hygiene.

[72]  David G. Watson,et al.  A Molecular Mechanism for Eflornithine Resistance in African Trypanosomes , 2010, PLoS pathogens.

[73]  M. Ouellette,et al.  Leishmaniasis: drugs in the clinic, resistance and new developments. , 2004, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[74]  Mark R. Viant,et al.  MI-Pack: Increased confidence of metabolite identification in mass spectra by integrating accurate masses and metabolic pathways , 2010 .

[75]  Yi Liu,et al.  Postulating Modes of Action of Compounds with Antimicrobial Activities through Metabolomics Analysis , 2010 .

[76]  Michael P. Barrett,et al.  Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei , 2012, PLoS neglected tropical diseases.

[77]  김삼묘,et al.  “Bioinformatics” 특집을 내면서 , 2000 .

[78]  Kristian Hovde Liland,et al.  Multivariate methods in metabolomics – from pre-processing to dimension reduction and statistical analysis , 2011 .

[79]  Jordi Duran,et al.  A Guideline to Univariate Statistical Analysis for LC/MS-Based Untargeted Metabolomics-Derived Data , 2012, Metabolites.

[80]  K. Silamut,et al.  Artemisinin resistance in Plasmodium falciparum malaria. , 2009, The New England journal of medicine.

[81]  S. Meshnick.  Perspective: Artemisinin-Resistant Malaria and the Wolf , 2012, The American journal of tropical medicine and hygiene.