The interaction of beta-lactam compounds with chromosomally mediated enzymes: relations to the molecular structure.

The interaction of 25 beta-lactam compounds with both chromosomally mediated beta-lactamases from Enterobacter cloacae and Citrobacter freundii was studied by enzyme kinetics. All the penams, cephems, and the penem Sch 29482 revealed 'competitive inhibition' of both enzymes. The penem required a preincubation period of approximately 5 min before reaching a state of equilibrium between the active and the inactive enzyme. Except for the recently developed compound HR 810, newer cephalosporins generally exhibited a high affinity for both enzymes. Consistent with earlier findings latamoxef, N-formimidoyl thienamycin, aztreonam and clavulanic acid showed a time dependent inhibition of the enzyme activity. These findings suggest a more complex reaction scheme including a second reversible complex. The last-mentioned compounds share one structural property: the modification or even the loss of the ring fused to the beta-lactam ring. Among these compounds, clavulanic acid exhibited the lowest affinity for the enzymes. It seems likely that the affinity of beta-lactam compounds is mainly influenced by the nature of the substituents.