Biomimetic hydrolysis of penicillin G catalyzed by dinuclear zinc(II) complexes: structure-activity correlations in beta-lactamase model systems.
A series of highly preorganized pyrazolate-based dinuclear zinc complexes has been studied as functional synthetic analogues of metallo-beta-lactamases, a class of bacterial enzymes that cause serious clinical problems because of their degradation of common beta-lactam antibiotics. We have investigated the hydrolytic cleavage of penicillin G mediated by the different dinuclear zinc complexes, and have deduced structure-activity correlations. While cooperative effects of the adjacent metal ions might be operative, these are found to either enhance or diminish beta-lactamase activity with respect to a single free zinc. Drastic differences in activity are ascribed to a lack of accessible binding sites after incorporation of the substrate within the bimetallic pocket of 2 and 4, whereas partial detachment of hemilabile ligand side arms in 1 and 3 opens up available coordination sites for nucleophile activation and/or for binding and polarisation of the beta-lactam amide oxygen atom. This interpretation has been corroborated by NMR spectroscopic and mass spectrometric evidence as well as by X-ray crystallography of several adducts formed between the pyrazolate-based dinuclear zinc scaffolds and the small substrate analogue oxazetidinylacetate (oaa), 5-7. In all adducts, the carboxylate group of oaa is the primary anchoring site and is nested in a bridging position within the bimetallic pocket. However, zinc binding of the beta-lactam amide oxygen atom has been confirmed crystallographically for the first time in 7, in which additional open-site coordination sites are available.
Bauer-Siebenlist
Bernhard
B
Institut für Anorganische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 4, 37077 Göttingen, Germany.
Dechert
Sebastian
S
Meyer
Franc
F
D002384:Catalysis; D018360:Crystallography, X-Ray; D006868:Hydrolysis; D008958:Models, Molecular; D018716:Molecular Mimicry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010400:Penicillin G / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism*; D001618:beta-Lactamases / Q000378:metabolism*
D001618:beta-Lactamases; D015032:Zinc; D010400:Penicillin G