title: Binding of β-lactam antibiotics to a bioinspired dizinc complex reminiscent of the active site of metallo-β-lactamases.
abstract: Metallo-β-lactamases (mβls) cause bacterial resistance toward a broad spectrum of β-lactam antibiotics by catalyzing the hydrolytic cleavage of the four-membered β-lactam ring, thus inactivating the drug. Minutiae of the mechanism of these enzymes are still not well understood, and reports about binding studies of the substrates to the enzymes as well as to synthetic model systems are rare. Here we report a new pyrazolate-based bioinspired dizinc complex (1) reminiscent of the active site of binuclear mβls. Since 1 does not mediate hydrolytic degradation of β-lactams, the binding of a series of common β-lactam antibiotics (benzylpenicillin, cephalotin, 6-aminopenicillanic acid, ampicillin) as well as the inhibitor sulbactam and the simplest β-lactam, 2-azetidinone, to the dizinc core of 1 could now be studied in detail by NMR and IR spectroscopy as well as mass spectrometry. X-ray crystallographic information was obtained for 1 and its complexes with 2-azetidinone (2) and sulbactam (3); the latter represents the first structurally characterized dizinc complex with a bound β-lactam drug. While 2-azetidinone was found deprotonated and bridging in the clamp of the two zinc ions in 2, in 3 and all other cases the substrates preferentially bind via their carboxylate group within the bimetallic pocket. The relevance of this binding mode for mβls and consequences for the design of functional model systems are discussed.
authors.affiliation: Institute of Inorganic Chemistry, Georg-August-University Göttingen, Tammannstrasse 4, 37077 Göttingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Wöckel
authors.forename: Joanna
authors.initials: J
authors.lastname: Galezowska
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dechert
authors.forename: Franc
authors.initials: F
authors.lastname: Meyer
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001419:Bacteria / Q000737:chemistry / Q000201:enzymology; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism; D047090:beta-Lactams / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D056831:Coordination Complexes; D011720:Pyrazoles; D047090:beta-Lactams; D001618:beta-Lactamases; D015032:Zinc