Inhibition of class C β-lactamases by (1'R,6R)-6-(1'-hydroxy)benzylpenicillanic acid SS-dioxide

Abstract

β-lactamases, enzymes that catalyse the hydrolysis of the β-lactam ring in β-lactam antibiotics, are divided into three classes, A, B and C, on the basis of the structures so far determined. There are relatively few effective inhibitors of class C β-lactamases. A β-lactam sulphone with a hydroxybenzyl side chain, namely (1'R,6R)-6-(1'-hydroxy)benzylpenicillanic acid SS-dioxide (I), has now been studied. The sulphone is a good mechanism-based inhibitor of class C β-lactamases. At pH 8, the inhibition of a Pseudomonas β-lactamase is irreversible, and proceeds at a rate that is about one-tenth the rate of concurrent hydrolysis. The labelled enzyme has enhanced u.v. absorption and is probably an enamine. At a lower pH, however, inhibition is transitory.