Printed in Great Britain A2- and A3-cephalosporins, penicillinate and 6-unsubstituted penems Intrinsic reactivity and interaction with P-lactamases and D-alanyl-D-alanine-cleaving serine peptidases

The intrinsic reactivity of A2- and A3-deacetoxy-7-phenylacetamidocephalosporanates, penicillanate, unsubstituted, 2-methyl- and 2-phenyl-penems and other,J-lactam antibiotics has been expressed in terms of the second-order rate constant (M-1 * s-'(OH-)) for the hydrolysis of the /3-lactam amide bond by OH- at 37 ° C. The values thus obtained have been compared with the second-order rate constants (M-1 * s-'(enzyme)) for the opening of the same,J-lactam amide bond during interaction with the fJ-lactamases of Streptomyces albus G and Actinomadura R39 and the D-alanyl-D-alanine-cleaving serine peptidases of Streptomyces R61 and Actinomadura R39. Depending on the cases, the accelerating effect due to enzyme action and expressed by the ratio m-Is-I(enzyme)/M-*Is-I(OH-) varies from less than 2 to more than 1 x 106. The primary parameter that governs enzyme action is the goodness of fit of the fJ-lactam molecule to the enzyme cavity rather than its intrinsic reactivity. With the D-alanyl-D-alanine-cleaving serine peptidases, the three penems studied form intermediate complexes characterized by very short half lives of 14-100s, values significantly lower than those exhibited by most fl-lactam compounds. 16-Lactam compounds with widely varying bi-cyclic fused-ring systems and substituents have been synthesized or isolated from natural sources (Hamil