Synthesis of Bulky β-Lactams for Inhibition of Cell Surface β-Lactamase Activity

Procedures are described for the preparation of a series of compounds consisting of methicillin linked to β-cyclodextrin through variable hydrophilic linkers. β-Cyclodextrin was coupled to the antibiotic methicillin to prevent the antibiotic from permeating the outer membranes of bacteria. Stoichiometric oxidation of the β-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 β-lactamase. The length of the spacer arm between β-cyclodextrin and methicillin was crucial in binding β-lactamase and inhibiting activity. Compounds with longer spacers were effective inhibitors of β-lactamase. We have deduced that the length of the spacer should be greater than 16 Å for optimum inhibition of β-lactamase.