title: Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase.
abstract: OBJECTIVE
  (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action.
  
  
  METHODS
  Biomimetic Pictet-Spengler or Bischler-Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds.
  
  
  RESULTS
  In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis.
  
  
  CONCLUSIONS
  As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis.
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors: Juan D
authors: JD
authors: Guzman
authors: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors: Thomas
authors: T
authors: Pesnot
authors: Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Carrera 30 No. 45-03, Bogotá, Colombia.
authors: Diana A
authors: DA
authors: Barrera
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors: Heledd M
authors: HM
authors: Davies
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors: Eleanor
authors: E
authors: McMahon
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors: Dimitrios
authors: D
authors: Evangelopoulos
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors: Parisa N
authors: PN
authors: Mortazavi
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors: Tulika
authors: T
authors: Munshi
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors: Arundhati
authors: A
authors: Maitra
authors: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors: Eleanor D
authors: ED
authors: Lamming
authors: Drug Discovery Group, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors: Richard
authors: R
authors: Angell
authors: The Advanced Centre for Biochemical Engineering, University College London, Gordon Street, London WC1H 0AH, UK.
authors: Markus C
authors: MC
authors: Gershater
authors: Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors: Joanna M
authors: JM
authors: Redmond
authors: Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors: Deborah
authors: D
authors: Needham
authors: Drug Discovery Group, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors: John M
authors: JM
authors: Ward
authors: Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Carrera 30 No. 45-03, Bogotá, Colombia.
authors: Luis E
authors: LE
authors: Cuca
authors: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors: Helen C
authors: HC
authors: Hailes
authors: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK s.bhakta@bbk.ac.uk sanjib.bhakta@ucl.ac.uk.
authors: Sanjib
authors: S
authors: Bhakta
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D010453:Peptide Synthases / Q000009:adverse effects*; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D044005:Tetrahydroisoquinolines; D010453:Peptide Synthases; C554750:MurE protein, Mycobacterium tuberculosis
keywords: Mycobacterium tuberculosis; SPOTi; TB; aporphine alkaloids; cell wall peptidoglycan; drug resistance; tuberculosis
references: Nature. 2001 Feb 22;409(6823):1007-11
references: 11234002
references: FEMS Microbiol Lett. 2001 Mar 15;196(2):93-8
references: 11267762
references: Mol Microbiol. 2003 Apr;48(1):77-84
references: 12657046
references: J Nat Prod. 2003 Jun;66(6):823-8
references: 12828469
references: Experientia. 1962 Feb 15;18:64-6
references: 13911190
references: Rapid Commun Mass Spectrom. 2004;18(5):523-8
references: 14978796
references: Chem Rev. 2004 Jul;104(7):3341-70
references: 15250744
references: Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16789-94
references: 15557000
references: J Nat Prod. 2004 Dec;67(12):1961-8
references: 15620234
references: Genes Dev. 2005 Jul 15;19(14):1692-704
references: 15985609
references: J Chem Inf Model. 2006 Mar-Apr;46(2):665-76
references: 16562997
references: Mol Microbiol. 2006 Oct;62(1):132-47
references: 16942606
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D455-8
references: 18974178
references: J Nat Prod. 2009 Mar 27;72(3):360-5
references: 19093848
references: Fitoterapia. 2009 Apr;80(3):149-63
references: 19344681
references: J Ethnopharmacol. 2009 Aug 17;125(1):47-50
references: 19573585
references: Am J Respir Crit Care Med. 2010 Jan 1;181(1):80-6
references: 19833824
references: Tuberculosis (Edinb). 2010 Jan;90(1):16-24
references: 19945347
references: Methods Mol Biol. 2010;642:193-201
references: 20401596
references: J Antimicrob Chemother. 2010 Oct;65(10):2101-7
references: 20719764
references: Protein Cell. 2010 Nov;1(11):1011-22
references: 21153518
references: Chem Commun (Camb). 2011 Mar 21;47(11):3242-4
references: 21270984
references: J Antimicrob Chemother. 2011 Aug;66(8):1766-72
references: 21622974
references: Int J Antimicrob Agents. 2012 Feb;39(2):124-9
references: 22079533
references: Lancet. 2012 Jan 21;379(9812):205
references: 22272391
references: J Antimicrob Chemother. 2012 Jun;67(6):1380-91
references: 22398649
references: Bioorg Med Chem Lett. 2012 Apr 15;22(8):2902-5
references: 22418278
references: Phytother Res. 2013 Jul;27(7):993-8
references: 22899555
references: J Med Chem. 1990 Jan;33(1):147-52
references: 2296014
references: Org Lett. 2012 Sep 21;14(18):4770-3
references: 22963079
references: PLoS One. 2013;8(3):e60143
references: 23555903
references: BMJ Open. 2013 Jun 20;3(6):null
references: 23794563
references: J Nat Prod. 1979 Mar;42(2):133-149
references: 27802380
references: J Antimicrob Chemother. 1986 Nov;18 Suppl D:31-41
references: 3542947
references: Am Rev Respir Dis. 1969 Oct;100(4):579-81
references: 4981706