MurD enzymes from different bacteria: evaluation of inhibitors.
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.
Univ Paris-Sud, Laboratoire des Enveloppes Bactériennes et Antibiotiques, UMR 8619, Orsay, F-91405, France.
Hélène
H
Barreteau
Izidor
I
Sosič
Samo
S
Turk
Jan
J
Humljan
Tihomir
T
Tomašić
Nace
N
Zidar
Mireille
M
Hervé
Audrey
A
Boniface
Lucija
L
Peterlin-Mašič
Danijel
D
Kikelj
Dominique
D
Mengin-Lecreulx
Stanislav
S
Gobec
Didier
D
Blanot
D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016133:Polymerase Chain Reaction
D004791:Enzyme Inhibitors; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase