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

Guzman, JD; Pesnot, T; Barrera, DA; Davies, HM; McMahon, E; Evangelopoulos, D; Mortazavi, PN; Munshi, T; Maitra, A; Lamming, ED; et al. Guzman, JD; Pesnot, T; Barrera, DA; Davies, HM; McMahon, E; Evangelopoulos, D; Mortazavi, PN; Munshi, T; Maitra, A; Lamming, ED; Angell, R; Gershater, MC; Redmond, JM; Needham, D; Ward, JM; Cuca, LE; Hailes, HC; Bhakta, S (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. https://doi.org/10.1093/jac/dkv010
SGUL Authors: Munshi, Tulika Kishanlal

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Abstract

Objectives (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.

Item Type: Article
Additional Information: © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Microbiology, 1115 Pharmacology And Pharmaceutical Sciences, 0605 Microbiology, 1108 Medical Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Journal of Antimicrobial Chemotherapy
Dates:
DateEvent
4 February 2015Published
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
G0801956Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G014426/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
URI: https://openaccess.sgul.ac.uk/id/eprint/107845
Publisher's version: https://doi.org/10.1093/jac/dkv010

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