A study of the nucleophilic attack of the beta-lactamic bond of antibiotics in water solution

The nucleophilic attack of a series of 19 beta -lactamic antibiotics (13 pe nicillins and six cephalosporins), as well as that of the clavulanic acid ( CLA), by a hydroxylic anion, is considered in water solution and in gas pha se. It is found that the tetrahedral intermediate formation does not occur spontaneously anymore in water solution, but the reaction has to overpass a n energy barrier due to the desolvation of the reactants. The desolvation e nergy barriers, as well as the tetrahedral complex formation energy in wate r solution are calculated into the PM3 semi-empirical approach and the supe rmolecule model. In the same way, the energy barriers for the beta -lactami c bond breaking and the final product formation energies are determined. Th e results are compared with those obtained previously for the same molecule s in the gas phase. The energy barrier heights as well as the formation energies found in water solution For the tetrahedral intermediates are seen to exhibit similar beh avior in the gas phase and in water solution, except in the case of CLA. Th is feature could perhaps explain the different behavior of CLA with respect to the D-alanyl-D-alanine-transferase acid some P-lactamases. (C) 2001 Els evier Science B.V, All rights reserved.