title: Structure-based design of a new series of D-glutamic acid based inhibitors of bacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD).
abstract: MurD ligase is one of the key enzymes participating in the intracellular steps of peptidoglycan biosynthesis and constitutes a viable target in the search for novel antibacterial drugs to combat bacterial drug-resistance. We have designed, synthesized, and evaluated a new series of D-glutamic acid-based Escherichia coli MurD inhibitors incorporating the 5-benzylidenethiazolidin-4-one scaffold. The crystal structure of 16 in the MurD active site has provided a good starting point for the design of structurally optimized inhibitors 73-75 endowed with improved MurD inhibitory potency (IC(50) between 3 and 7 μM). Inhibitors 74 and 75 showed weak activity against Gram-positive Staphylococcus aureus and Enterococcus faecalis. Compounds 73-75, with IC(50) values in the low micromolar range, represent the most potent D-Glu-based MurD inhibitors reported to date.
authors: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors: Tihomir
authors: T
authors: Tomasić
authors: Nace
authors: N
authors: Zidar
authors: Roman
authors: R
authors: Sink
authors: Andreja
authors: A
authors: Kovac
authors: Didier
authors: D
authors: Blanot
authors: Carlos
authors: C
authors: Contreras-Martel
authors: Andréa
authors: A
authors: Dessen
authors: Manica
authors: M
authors: Müller-Premru
authors: Anamarija
authors: A
authors: Zega
authors: Stanislav
authors: S
authors: Gobec
authors: Danijel
authors: D
authors: Kikelj
authors: Lucija Peterlin
authors: LP
authors: Masic