Comparative Inhibition of β-Lactamases by Novel β-Lactam Compounds

The β-lactamase-inhibiting activity of CP-45,899, 3,3-dimethyl-7-oxo-4-thia-1-azabicylo(3,2,0)heptane-2-carboxylic acid, 4,4-dioxide [2S-(2α,5α)], was investigated and compared with the β-lactamase-inhibiting activity of clavulanic acid and dicloxacillin. CP-45,899 was an effective inhibitor ofStaphylococcus aureus β-lactamase and of those β-lactamases of gram-negative bacteria which are primarily active against penicillins or equally active against penicillins and cephalosporins. The reaction of CP-45,899 with β-lactamases was a concentration- and time-dependent event. CP-45,899 acted as a competitive inhibitor of plasmid-mediatedS. aureus, Escherichia coli , andShigella sonnei β-lactamases and inducibleKlebsiella β-lactamase. CP-45,899 was a poor inhibitor of inducible or constitutive chromosomally mediated β-lactamases of indole-positiveProteus, Citrobacter , andEnterobacter . CP-45,899 had lower kinetic constants for inhibition of hydrolysis than did clavulanic acid against many of the β-lactamases which both inhibited.