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

Abstract

The Zn²⁺-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°C, 0.5 mol·dm^-3 ionic strength and in the presence of metal ions (Zn²⁺, Cd²⁺, Co²⁺, Cu²⁺, Ni²⁺ and Mn²⁺). 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 Cd²⁺-Tris and Zn²⁺-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.