Penetration of cephalosporins and corresponding 1-oxacephalosporins through the outer layer of Gram-negative bacteria and its contribution to antibacterial activity.

1-Oxacephalosporins had a higher ability to penetrate through the outer layer of the envelope of gram-negative bacteria than the corresponding cephalosporins. In spite of the liability of 1-oxa congeners to beta-lactamases, they attained higher periplasm concentrations at a given concentration outside the cells. The replacement of sulfur in the cephem nucleus by oxygen was accompanied by an increment of the hydrophilic character of the molecule, which suggests that this character was favorable for outer layer penetration. 1-Oxacephalosporins showed enhanced antibacterial activity in short-term measurement and exerted their antibacterial action at lower periplasm concentrations. Thus, the enhanced antibacterial activity of 1-oxacephalosporins seems to be due to their higher penetrability and their intrinsic inhibitory activity against the peptidoglycan biosynthesis system.