POTENT MECHANISM-BASED INHIBITION OF THE TEM-1 BETA-LACTAMASE BY NOVEL N-SULFONYLOXY BETA-LACTAMS

A novel class of N-sulfonyloxy beta-lactam molecules are described as potent mechanism-based inactivators for the bacterial TEM-1 beta-lactamase, a prototypic class A enzyme. These molecules inactivate the enzyme with k(inact)/K-i values in the range of 1-7 x 10(4) M(-1) s(-1) and partition ratios (i.e., k(cat)/k(inact)) of 2-7. The mechanism of action of these inactivators was investigated. These molecules acylate the active-site serine of the TEM-1 beta-lactamase, a process that results in the release of the sulfonate attached to the lactam nitrogen, giving rise to a proposed beta-amino cinnamoyl derivative as the inhibitory species. This species undergoes gradual hydrolysis with concomitant recovery of activity, the rate constants for which were evaluated.