The re
si
stance of bacteria to the normally lethal action of
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s i
s largely dueto the production of
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se
s that catalyze the hydroly
si
s of the
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ss of the
se enzyme
si
s a zinc-dependent metallo-
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se for which there are no clinically available inhibitor
s. The hydroly
si
sof cephalo
sporin
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s generate
s dihydrothiazine
s which
sub
sequently undergo i
somerizationat C6 by C-S bond cleavage and through the intermediacy of a thiol. The
se thiol
s can be trapped by the
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se from
Bacillus cereus, cau
sing inhibition of the enzyme. The rate of production of the thiolcorre
spond
s to the rate of inhibition, and the inhibition con
stant
s are in the micromolar range but varywith the nature of the cephalo
sporin derivative. NMR
studie
s have identified the
structure of the thiol
scau
sing inhibition and al
so
show that the thiol bind
s to the zinc ion, which in turn perturb
s the metal-bound hi
stidine
s. Inhibition i
s slowly removed a
s the thiol become
s oxidized or undergoe
s furtherdegradation. The thiol intermediate generated from cephalothin i
s a
slow binding inhibitor. There i
s noob
served inhibition from the analogou
s degradation product
s from penicillin
s.