Catalysis of Hydrolysis and Aminolysis of Non-classical β-Lactam Antibiotics by Metal Ions and Metal Chelates

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The Zn^<2+>-tris (hydroxymethyl)aminomethane (Tris) system has a great catalytic effect on the hydrolysis and aminolysis of some β-lactam antibiotics. In order to ascertain the mechanism of this catalysis we have analysed the effects of the β-lactam antibiotic structure. First we studied the kinetics of the decomposition of imipenem, SCH 29482,aztreonam and nocardicin A in aqueous solution of Tris at 35.0℃, 0.5 mol・dm^<-3> ionic strength and in the presence of metal ions (Zn^<2+>, Cd^<2+>, Co^<2+>, Cu^<2+>, Ni^<2+> and Mn^<2+>). From these studies, we conclude that Tris and metal ions (in separate solutions) exert a great catalytic effect on the hydrolysis of imipenem and SCH 29482. We suggest that in metal ion solutions a 1 : 1 complex is formed between the metal ion and β-lactam antibiotic, which is attacked by hydroxide ions.Studies of the degradation of the antibiotis studied in solutions of Tris and metal ions together indicate that the systems Cd^<2+>-Tris and Zn^<2+>-Tris have a great catalytic effect on the hydrolysis and aminolysis of imipenem and SCH 29482. we suggest that this catalysis takes place via a ternary complex in which the metal ion plays a double role by (a) placing the antibiotic and the Tris in the right position for the reaction and (b) lowering the pK_a of the hydroxide group of Tris, which is coordinated with the metal ion, generating a strong nucleophile.
社団法人日本薬学会の論文
1992-12-25