Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics
Guzman, Juan D. and Wube, A. and Evangelopoulos, Dimitrios and Gupta, Antima and Hufner, A. and Basavannacharya, Chandrakala and Rahman, M.M. and Thomaschitz, C. and Bauer, R. and McHugh, T.D. and Nobeli, Irilenia and Prieto, J.M. and Gibbons, S. and Bucar, F. and Bhakta, Sanjib (2011) Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. Journal of Antimicrobial Chemotherapy 66 (8), pp. 1766-1772. ISSN 0305-7453.
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.
|Keyword(s) / Subject(s):||4-quinolones, Mur ligase inhibitors, M. tuberculosis|
|School:||Birkbeck Schools and Departments > School of Science > Biological Sciences|
|Research Centre:||Bioinformatics, Bloomsbury Centre for, Structural Molecular Biology, Institute of (ISMB)|
|Date Deposited:||12 Aug 2011 11:37|
|Last Modified:||07 Dec 2016 15:00|
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