Inactivation of beta-lactamases by sulbactam and enhanced clinical activity due to target-site binding of the combination of sulbactam and ampicillin.
In addition to the beta-lactamase-inactivation activity of sulbactam, a stronger bactericidal activity has been confirmed with sulbactam/ampicillin than with either antibiotic alone. To clarify this latter mechanism, binding affinities of the combination drug were compared with those of ampicillin and sulbactam alone against the PBPs of E. coli, S. aureus, P. vulgaris and H. influenzae. Ampicillin showed the highest binding activity to the PBP fraction essential for septum formation such as PBP3 of E. coli, whereas sulbactam manifested the strongest affinity for the PBP fraction necessary for cell elongation such as PBP1a of E. coli. Sulbactam/ampicillin bound strongly to both PBP fractions. Light microscopy and scanning electronmicroscopy of these bacteria grown in the presence of the antibiotics revealed that more rapid formation of bulge or spheroplast forms of the cells are seen in the presence of small amounts of sulbactam/ampicillin compared to larger amounts of each drug alone. It is concluded that sulbactam/ampicillin, by synergistic inhibition of PBP fractions essential for bacterial cell division, can manifest a stronger bactericidal effect on Gram-positive and Gram-negative bacteria than each drug alone, not only in beta-lactamase-producing strains but also in ampicillin-sensitive strains.
Yokota
T
T
Department of Bacteriology, Juntendo University School of Medicine, Tokyo, Japan.
D000667:Ampicillin / Q000008:administration & dosage* / Q000378:metabolism; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D001426:Bacterial Proteins; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000008:administration & dosage; D006602:Hexosyltransferases; D008855:Microscopy, Electron, Scanning; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D013407:Sulbactam / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D065093:beta-Lactamase Inhibitors; D000667:Ampicillin; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D013407:Sulbactam