Synthesis of Bulky @ - Lactams for Inhibition of Cell Surface @ - Lac t amase Activity

Procedures are described for the preparation of a series of compounds consisting of methicillin linked to 0-cyclodextrin through variable hydrophilic linkers. P-Cyclodextrin was coupled to the antibiotic methicillin to prevent the antibiotic from permeating the outer membranes of bacteria. Stoichiometric oxidation of the P-cyclodextrin with sodium metaperiodate provided a functional group for coupling to the linker. Methicillin was coupled to the linker via its carboxyl group. These compounds were tested for activity toward purified P-lactamase. The length of the spacer arm between P-cyclodextrin and methicillin was crucial in binding 0-lactamase and inhibiting activity. Compounds with longer spacers were effective inhibitors of /3-lactamase. We have deduced that the length of the spacer should be greater than 16 A for optimum inhibition of 6-lactamase.