title: Structural basis of the inhibition of class A beta-lactamases and penicillin-binding proteins by 6-beta-iodopenicillanate.
abstract: 6-Beta-halogenopenicillanates are powerful, irreversible inhibitors of various beta-lactamases and penicillin-binding proteins. Upon acylation of these enzymes, the inhibitors are thought to undergo a structural rearrangement associated with the departure of the iodide and formation of a dihydrothiazine ring, but, to date, no structural evidence has proven this. 6-Beta-iodopenicillanic acid (BIP) is shown here to be an active antibiotic against various bacterial strains and an effective inhibitor of the class A beta-lactamase of Bacillus subtilis BS3 (BS3) and the D,D-peptidase of Actinomadura R39 (R39). Crystals of BS3 and of R39 were soaked with a solution of BIP and their structures solved at 1.65 and 2.2 A, respectively. The beta-lactam and the thiazolidine rings of BIP are indeed found to be fused into a dihydrothiazine ring that can adopt two stable conformations at these active sites. The rearranged BIP is observed in one conformation in the BS3 active site and in two monomers of the asymmetric unit of R39, and is observed in the other conformation in the other two monomers of the asymmetric unit of R39. The BS3 structure reveals a new mode of carboxylate interaction with a class A beta-lactamase active site that should be of interest in future inhibitor design.
authors.affiliation: Centre d'Ingénierie des Protéines and Centre de Recherches du Cyclotron, Université de Liège, B-4000 Sart Tilman, Belgium. eric.sauvage@ulg.ac.be
authors.forename: Eric
authors.initials: E
authors.lastname: Sauvage
authors.forename: Astrid
authors.initials: A
authors.lastname: Zervosen
authors.forename: Georges
authors.initials: G
authors.lastname: Dive
authors.forename: Raphael
authors.initials: R
authors.lastname: Herman
authors.forename: Ana
authors.initials: A
authors.lastname: Amoroso
authors.forename: Bernard
authors.initials: B
authors.lastname: Joris
authors.forename: Eveline
authors.initials: E
authors.lastname: Fonzé
authors.forename: Rex F
authors.initials: RF
authors.lastname: Pratt
authors.forename: André
authors.initials: A
authors.lastname: Luxen
authors.forename: Paulette
authors.initials: P
authors.lastname: Charlier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Kerff
mesh_terms: D000192:Actinomycetales / Q000201:enzymology*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001412:Bacillus subtilis / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D046915:Penicillin-Binding Proteins; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; C031528:6-iodopenicillanic acid; D001618:beta-Lactamases