The INTERPLAY OF Β‐LACTAMASES AND INTRINSIC FACTORS IN THE RESISTANCE OF GRAM‐ NEGATIVE BACTERIA TO PENICILLINS AND CEPHALOSPORINS*

Inhibition of Escherichia coli K-12 by β-Lactam Antibiotics With Poor Antibacterial Activity: Interaction of Permeability And Intrinsic Activity Against Penicillin-Binding Proteins

“…Cephaloridine, on the other hand, is equally active against the PBPs of both E. coli strains and has the same activity against intact bacteria of both strains, indicating that this derivative has little difficulty penetrating to the target, a result substantiated by other work (3,16,17). DISCUSSION The results described in this paper show that the lack of antibacterial activity of methicillin, cloxacilhin, 1078/1/1 and, to a lesser extent, penicillin G against non-f-lactamase-producing strains of E. coli K-12 is due to impenetrability of the compounds through the outer membrane of the bacterial envelope.…”

“…The data in Table 2 indicate that the "target" proteins in both E. coli DCO and DC2 are identical and show, moreover, that the compounds which are antibacterially inactive against the wild-type E. coli strain owe this inactivity to an inability to penetrate the envelope to the PBPs located in the cytoplasmic membrane (16,17,21). Cephaloridine, on the other hand, is equally active against the PBPs of both E. coli strains and has the same activity against intact bacteria of both strains, indicating that this derivative has little difficulty penetrating to the target, a result substantiated by other work (3,16,17).…”

“…The change in the permeability properties of these mutants was partially substantiated by "crypticity" measurements (16)(17)(18)27) but it is impossible to know how permeable such mutants actually are and, furthermore, the possibility of a change in the sensitivity of the /8-lactam target proteins was not excluded.…”

“…Mutants of E. coli K-12 and other gram-negative bacteria that have been selected for increased sensitivity to a particular antibiotic are frequently found to exhibit increased sensitivity to a wide range of antibacterial agents (16)(17)(18). Such mutants are often regarded as "permeability" mutants having lesions affecting the integrity of the outer membrane and thereby allowing easier access of antibiotics into the bacterial cell.…”

“…First, the ability of the compound to bind to and inhibit the "lethal" target penicillin-binding proteins (PBPs) located in the inner or cytoplasmic membrane (20,21). Second, the antibiotic must penetrate the permeability barrier afforded by the outer membrane of the bacterial envelope (17,18), and third, the compound must be resistant to any periplasmically located 8-lactamase (4,17).…”