Catalysis of Hydrolysis and Aminolysis of Non-classical /J-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 /Mactam antibiotics. In order to ascertain the mechanism of this catalysis we have analysed the effects of the /Mactam 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 P-lactam antibiotic, which is attacked by hydroxide ions. Studies of the degradation of the antibiotics 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& of the hydroxide group of Tris, which is coordinated with the metal ion, generating a strong nucleophile. © 1992, The Pharmaceutical Society of Japan. All rights reserved.