Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: Antibacterial activity, molecular docking and inhibition kinetics

Juan David Guzman, Abraham Wube, Dimitrios Evangelopoulos, Antima Gupta, Antje Hüfner, Chandrakala Basavannacharya, Md Mukhleshur Rahman, Christina Thomaschitz, Rudolf Bauer, Timothy Daniel McHugh, Irene Nobeli, Jose M. Prieto, Simon Gibbons, Franz Bucar, Sanjib Bhakta

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Abstract

Objectives: The aim of this study was to comprehensively evaluate the antibacterial activity and MurE inhibition of a set of N-methyl-2-alkenyl-4-quinolones found to inhibit the growth of fast-growing mycobacteria. Methods: Using the spot culture growth inhibition assay, MICs were determined for Mycobacterium tuberculosis H37Rv, Mycobacterium bovis BCG and Mycobacterium smegmatis mc2155. MICs were determined for Mycobacterium fortuitum, Mycobacterium phlei, methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa using microplate dilution assays. Inhibition of M. tuberculosis MurE ligase activity was determined both by colorimetric and HPLC methods. Computational modelling and binding prediction of the quinolones in the MurE structure was performed using Glide. Kinetic experiments were conducted for understanding possible competitive relations of the quinolones with the endogenous substrates of MurE ligase. Results: The novel synthetic N-methyl-2-alkenyl-4-quinolones were found to be growth inhibitors of M. tuberculosis and rapid-growing mycobacteria as well as methicillin-resistant S. aureus, while showing no inhibition for E. coli and P. aeruginosa. The quinolones were found to be inhibitory to MurE ligase of M. tuberculosis in the micromolar range (IC50 ~40-200 μM) when assayed either spectroscopically or by HPLC. Computational docking of the quinolones on the published M. tuberculosis MurE crystal structure suggested that the uracil recognition site is a probable binding site for the quinolones. Conclusions: N-methyl-2-alkenyl-4-quinolones are inhibitors of mycobacterial and staphylococcal growth, and show MurE ligase inhibition. Therefore, they are considered as a starting point for the development of increased affinity MurE activity disruptors.

Original languageEnglish
Article numberdkr203
Pages (from-to)1766-1772
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume66
Issue number8
Early online date28 May 2011
DOIs
Publication statusPublished - Aug 2011

Keywords

  • 4-quinolones
  • M. tuberculosis
  • Mur ligase inhibitors

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