A. Bulychev et al., POTENT MECHANISM-BASED INHIBITION OF THE TEM-1 BETA-LACTAMASE BY NOVEL N-SULFONYLOXY BETA-LACTAMS, Journal of the American Chemical Society, 117(22), 1995, pp. 5938-5943
A novel class of N-sulfonyloxy beta-lactam molecules are described as
potent mechanism-based inactivators for the bacterial TEM-1 beta-lacta
mase, a prototypic class A enzyme. These molecules inactivate the enzy
me with k(inact)/K-i values in the range of 1-7 x 10(4) M(-1) s(-1) an
d partition ratios (i.e., k(cat)/k(inact)) of 2-7. The mechanism of ac
tion of these inactivators was investigated. These molecules acylate t
he active-site serine of the TEM-1 beta-lactamase, a process that resu
lts in the release of the sulfonate attached to the lactam nitrogen, g
iving rise to a proposed beta-amino cinnamoyl derivative as the inhibi
tory species. This species undergoes gradual hydrolysis with concomita
nt recovery of activity, the rate constants for which were evaluated.