The Effect of the Carboxy Group on the Chemical and β-Lactamase Reactivity of β-Lactam Antibiotics

Andrew P. Laws, Michael I. Page

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Abstract

Kinetic parameters are reported for the Bacillus cereus β-lactamase I and β-lactamase II catalysed hydrolysis of esters and lactones of penicillins and cephalosporins. These are compared with the second-order rate constants for the hydroxide-ion catalysed hydrolysis of the same derivatives. The second-order rate constant, kcat/Km, for the hydrolysis of the cephalosporin lactone catalysed by β-lactamase I is 50 times greater than that for an analogous cephalosporin and is 3 × 10 4 times greater than that for hydroxide-ion catalysed hydrolysis, a ratio similar to that for cephalosporins with a carboxylate group at C-4. The methyl ester of benzyl penicillin, but not the corresponding cephalosporanate, is a substrate for β-lactamase I. All ester derivatives are much poorer substrates for β-lactamase II. The cephalosporin lactone and, to a lesser extent, the methyl ester of benzyl penicillin can obviously bind to β-lactamase I even though they do not possess a formal anionic site at C-4 and C-3 respectively. The esterification of the carboxy group at C-3 in penicillins induces neighbouring-group participation by the C-6 acylamido side chain to give an oxazolinone intermediate. This is attributed to different Brönsted β19 dependency for alkaline hydrolysis and intramolecular acylamido participation, which exhibits rate limiting C-N bond fission of the β-lactam.

Original languageEnglish
Pages (from-to)1577-1581
Number of pages5
JournalJournal of the Chemical Society, Perkin Transactions 2
Issue number10
DOIs
Publication statusPublished - Oct 1989

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Lactams
Cephalosporins
Hydrolysis
Penicillins
Anti-Bacterial Agents
Esters
Lactones
Rate constants
Bacillus cereus
Derivatives
Esterification
Substrates
Kinetic parameters

Cite this

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title = "The Effect of the Carboxy Group on the Chemical and β-Lactamase Reactivity of β-Lactam Antibiotics",
abstract = "Kinetic parameters are reported for the Bacillus cereus β-lactamase I and β-lactamase II catalysed hydrolysis of esters and lactones of penicillins and cephalosporins. These are compared with the second-order rate constants for the hydroxide-ion catalysed hydrolysis of the same derivatives. The second-order rate constant, kcat/Km, for the hydrolysis of the cephalosporin lactone catalysed by β-lactamase I is 50 times greater than that for an analogous cephalosporin and is 3 × 10 4 times greater than that for hydroxide-ion catalysed hydrolysis, a ratio similar to that for cephalosporins with a carboxylate group at C-4. The methyl ester of benzyl penicillin, but not the corresponding cephalosporanate, is a substrate for β-lactamase I. All ester derivatives are much poorer substrates for β-lactamase II. The cephalosporin lactone and, to a lesser extent, the methyl ester of benzyl penicillin can obviously bind to β-lactamase I even though they do not possess a formal anionic site at C-4 and C-3 respectively. The esterification of the carboxy group at C-3 in penicillins induces neighbouring-group participation by the C-6 acylamido side chain to give an oxazolinone intermediate. This is attributed to different Br{\"o}nsted β19 dependency for alkaline hydrolysis and intramolecular acylamido participation, which exhibits rate limiting C-N bond fission of the β-lactam.",
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