title: Second-generation sulfonamide inhibitors of D-glutamic acid-adding enzyme: activity optimisation with conformationally rigid analogues of D-glutamic acid.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.forename: Hélène
authors.initials: H
authors.lastname: Barreteau
authors.forename: Mihael
authors.initials: M
authors.lastname: Simčič
authors.forename: Roman
authors.initials: R
authors.lastname: Sink
authors.forename: Jožko
authors.initials: J
authors.lastname: Cesar
authors.forename: Anamarija
authors.initials: A
authors.lastname: Zega
authors.forename: Simona Golič
authors.initials: SG
authors.lastname: Grdadolnik
authors.forename: Carlos
authors.initials: C
authors.lastname: Contreras-Martel
authors.forename: Andréa
authors.initials: A
authors.lastname: Dessen
authors.forename: Ana
authors.initials: A
authors.lastname: Amoroso
authors.forename: Bernard
authors.initials: B
authors.lastname: Joris
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004926:Escherichia coli / Q000737:chemistry* / Q000201:enzymology; D018698:Glutamic Acid / Q000737:chemistry*; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D018698:Glutamic Acid; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase