Codex @codex  0

An enzyme that hydrolyzes the beta-lactam ring of susceptible antibiotics. Substrate specificity and catalytic mechanisms vary among classes and variants.

A beta-lactam antibiotic with bulky substituents whose susceptibility to hydrolysis depends on the particular beta-lactamase.

The catalytic serine residue supplies a nucleophile: its side-chain oxygen attacks the carbonyl carbon of the beta-lactam ring. This generates a tetrahedral intermediate, followed by opening of the ring and formation of a covalent acyl-enzyme intermediate. Subsequent attack by activated water hydrolyzes that intermediate and regenerates the enzyme. The serine residue performs covalent catalysis and is regenerated, rather than being consumed as a reagent.

Bond c, the carbonyl-carbon–nitrogen bond within the four-membered beta-lactam ring, is cleaved. Hydrolysis opens the cyclic amide; it does not cut the side-chain amide or a carbon–carbon bond. The resulting open-ring product no longer has the intact beta-lactam pharmacophore required for its usual antibacterial action.

The bulky substituents of ceftazidime can hinder productive entry into the more restricted TEM-1 active site. A wider entrance in TEM-52 could accommodate this substrate and allow its beta-lactam ring to be hydrolyzed. The prediction is reduced susceptibility of TEM-52-expressing bacteria compared with matched TEM-1-expressing bacteria. This is a mechanistic prediction, not a quantitative conclusion from the penicillin G data: entry alone does not guarantee efficient catalytic chemistry for a different substrate. Test ceftazidime hydrolysis directly and measure its minimum inhibitory concentration in an otherwise matched bacterial background, controlling enzyme expression, growth, drug entry and other resistance mechanisms.

A beta-lactam antibiotic used as a substrate in comparisons of beta-lactamase kinetics.