[en] D-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities.
Disciplines :
Microbiology
Author, co-author :
Sosic, Izidor
Barreteau, Helene
Simcic, Mihael
Sink, Roman
Cesar, Jozko
Zega, Anamarija
Grdadolnik, Simona Golic
Contreras-Martel, Carlos
Dessen, Andrea
Amoroso, Ana Maria ; Université de Liège > Département des sciences de la vie > Centre d'ingénierie des protéines
Joris, Bernard ; Université de Liège > Département des sciences de la vie > Physiologie et génétique bactériennes
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