Hydrolysis of β-Lactam Antibiotics Catalyzed by Dinuclear Zinc(II) Complexes:  Functional Mimics of Metallo-β-lactamases

Abstract

Three stable dinuclear zinc(II) complexes, [Zn 2 L 1 (μ-NO 3 )(NO 3 ) 2 ] and [Zn 2 L 1 (μ-OMe)(NO 3 ) 2 ], where L 1 is 2,6-bis{[ N -(2-dimethylaminoethyl)- N -methyl]aminomethyl}-4-methylphenolate, and [Zn 2 L 2 (NO 3 ) 3 ], where L 2 is 2-{[ N -(2-dimethylaminoethyl)- N -methyl]aminomethyl}-4-bromo-6-{[ N ‘ -2-(2‘-pyridyl)ethyl]aminomethyl}phenolate, were synthesized and characterized in the solid state and in aqueous solution. These complexes catalyze the hydrolysis of penicillin G and nitrocefin, serving as functional synthetic analogues of the metallo-β-lactamases, bacterial enzymes responsible for antibiotic resistance. The mechanism of the hydrolysis was studied in detail for the catalyst precursor [Zn 2 L 1 (μ-NO 3 )(NO 3 ) 2 ], which converts into [Zn 2 L 1 (μ-OH)(NO 3 ) n (sol) 2 - n ] (2 - n )+ in the presence of water. The complex [Zn 2 L 1 (μ-OH)(NO 3 ) 2 ] ( n = 2) was characterized in the solid state. Initial coordination of the substrate carboxylate group is followed by the rate-limiting nucleophilic attack of the bridging hydroxide at the β-lactam carbonyl group in aqueous solution. The product is formed upon fast protonation of the intermediate. Mononuclear complexes Zn(cyclen)(NO 3 ) 2 and Zn(bpta)(NO 3 ) 2 are as reactive in the β-lactam hydrolysis as the dinuclear complexes. Consequently, the second zinc ion is not required for catalytic activity.