| beta-Lactam antibiotics are used for the treatment of bacterial infections caused by susceptible organisms and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. Bacterial production of a class of enzymes, beta-lactamases, is responsible for resistance towards beta-lactam antibiotics. These enzymes catalyze hydrolytic cleavage of the beta-lactam ring of the antibiotic and render them ineffective. One approach towards overcoming beta-lactamase induced-resistance employs beta-lactamase inhibitors. Based on the evidence that acyl phosph(on)ates rapidly acylate the active site of serine beta-lactamases and that the leaving group phosphate moiety interacts strongly with the active site of these enzymes, ketophosph(on)ates with an amido side chain were evaluated as a novel class of inhibitors of serine beta-lactamases. To further optimize a lead compound obtained from the above theme hydrophobic moieties were incorporated. A class of aryl ketophosphonates were also evaluated as inhibitors of serine beta-lactamases. On consideration of the free-energy of ligand binding to the Escherichia coli OXA-1 enzyme, it is evident that successive incorporation of hydrophobic substituents increased their binding affinity. Additivity of the effects of hydrophobic substituents was demonstrated. Models of these ligands at the active site showed that they might display a wide range of interactions with the enzyme.; Stable analogues of the transition state of the reaction of (di)acyl phosphates with the serine beta-lactamases, beta-benzyl beta-hydroxyethyl phosphonate monoesters were evaluated as inhibitors of serine beta-lactamases. The interactions of these ligands at the active site of E. coli OXA-1 beta-lactamase were explored by molecular modeling.; A series of cephalosporanates with 7beta-N-hydroxyamido/amino or a 7-oximino substituents, prepared by J. Buynak et al. (Southern Methodist University), was evaluated as inhibitors of serine beta-lactamases. Also included in this series of compounds were 7-oximino cephalosporin sulfones, with and without a leaving group at the 3' position. The kinetics of the reactivity of these beta-lactams with serine beta-lactamases was studied. The N-OH group, in general, significantly reduced substrate turnover numbers and, in some instances, produced transient inhibition. |
