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    Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase

    Guzman, Juan D. and Pesnot, T. and Barrera, D.A. and Davies, H.M. and McMahon, E. and Evangelopoulos, Dimitrios and Mortazavi, Parisa Nakhostin and Munshi, Tulika and Maitra, Arundhati and Lamming, E.D. and Angell, R. and Gershater, M.C. and Redmond, J.M. and Needham, D. and Ward, J.M. and Cuca, L.E. and Hailes, H.C. and Bhakta, Sanjib (2015) Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase. Journal of Antimicrobial Chemotherapy 70 (6), pp. 1691-1703. ISSN 0305-7453.

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    Abstract

    - Objectives: (S)-leucoxine, isolated from a Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan was found to inhibit the growth of M. 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-tubercular action. - Methods: Biomimetic Pictet-Spengler or Bischler-Napieralski synthetic routes were employed followed by evaluation of the biological activity of the synthesised compounds. - Results: In this work, the synthesised tetrahydroisoquinolines were found to inhibit the growth of Mycobacterium tuberculosis H37Rv, 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 (MurE-IC50) was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism/s of action in M. tuberculosis.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): Tuberculosis (TB), Mycobacterium, drug resistance, cell-wall peptidoglycan, aporphine, alkaloids, SPOTi
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 09 Feb 2015 11:17
    Last Modified: 06 Dec 2016 11:17
    URI: http://eprints.bbk.ac.uk/id/eprint/11466

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