Catalysis of hydrolysis and aminolysis of non-classical beta-lactam antibiotics by metal ions and metal chelates.
The Zn(2+)-tris (hydroxymethyl)aminomethane (Tris) system has a great catalytic effect on the hydrolysis and aminolysis of some beta-lactam antibiotics. In order to ascertain the mechanism of this catalysis we have analysed the effects of the beta-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 degrees 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 beta-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 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 pKa of the hydroxide group of Tris, which is coordinated with the metal ion, generating a strong nucleophile.
Méndez
R
R
Departamento de Bioquímica y Biología Molecular, Facultades de Biología y Veterinaria, Universidad de León, Spain.
Alemany
T
T
Martín-Villacorta
J
J
D000588:Amines / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D002384:Catalysis; D002614:Chelating Agents / Q000494:pharmacology*; D004355:Drug Stability; D006868:Hydrolysis; D008670:Metals / Q000494:pharmacology*; D012996:Solutions; D014325:Tromethamine; D047090:beta-Lactams
D000588:Amines; D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D008670:Metals; D012996:Solutions; D047090:beta-Lactams; D014325:Tromethamine