title: Macrocycle-embedded β-lactams as novel inhibitors of the Penicillin Binding Protein PBP2a from MRSA.
abstract: Assuming that bicyclic β-lactams endowed with high conformational adaptability should more easily form acyl-enzyme complexes with PBP2a than the traditional antibiotics, we have prepared a series of bis-2-oxo-azetidinyl macrocycles as potential inhibitors. The compounds are formally "head-head" (HH) cyclodimers of 1-(ω-alkenoyl)-3-(S)-(ω'-alkenoylamino)-2-azetidinones, with various lengths of the alkene chains, obtained by two successive metathesis reactions using the Grubbs catalyst. All compounds behave as acylating inhibitors of PBP2a and one β-lactam (5c), embedded into the largest ring (32 atoms), features an activity close to that of Ceftobiprole. Conformational analyses, theoretical reactivity models and docking experiments in PBP2a cavity allow to propose a novel pharmacophore, i.e. the 3-(S)-acylamino-1-acyl-2-azetidinone ring, with the syn-conformation of the imide function, associated to a flexible macrocycle favoring the opening of the active site.
authors: Université de Liège (ULg), Centre d'Ingénierie des Protéines (CIP), Bâtiment B6, Allée du 6 Août, Sart-Tilman, B-4000 Liège, Belgium.
authors: Georges
authors: G
authors: Dive
authors: Camille
authors: C
authors: Bouillon
authors: Aline
authors: A
authors: Sliwa
authors: Bénédicte
authors: B
authors: Valet
authors: Olivier
authors: O
authors: Verlaine
authors: Eric
authors: E
authors: Sauvage
authors: Jacqueline
authors: J
authors: Marchand-Brynaert
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D047028:Macrocyclic Compounds; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; C478699:penicillin-binding protein 2a, Streptococcus; D010453:Peptide Synthases