MurD enzymes from different bacteria: evaluation of inhibitors |
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Authors: | Barreteau Hélène Sosič Izidor Turk Samo Humljan Jan Tomašić Tihomir Zidar Nace Hervé Mireille Boniface Audrey Peterlin-Mašič Lucija Kikelj Danijel Mengin-Lecreulx Dominique Gobec Stanislav Blanot Didier |
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Affiliation: | Univ Paris-Sud, Laboratoire des Enveloppes Bactériennes et Antibiotiques, UMR 8619, Orsay, F-91405, France. |
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Abstract: | D-Glutamic acid-adding enzyme (MurD ligase) catalyses the addition of D-glutamic acid to UDP-N-acetylmuramoyl-L-alanine, an essential cytoplasmic step in the pathway for bacterial cell-wall peptidoglycan synthesis. As such, it represents an important antibacterial drug-discovery target enzyme. Recently, several series of compounds have been synthesised and found to inhibit MurD from Escherichia coli, the best one having an IC(50) value of 8 μM. In the present work, we have tested 20 of these compounds against the MurD enzymes from Staphylococcus aureus, Streptococcus pneumoniae, Borrelia burgdorferi and Mycobacterium tuberculosis. Most of the E. coli MurD inhibitors appeared less efficient against the four other orthologues. This divergent result can be explained by the differences in amino acid sequences and topologies of the active sites of the MurD ligases studied. |
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