178483-83-5Relevant academic research and scientific papers
?-LACTONE COMPOUNDS
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Paragraph 00163-00165; 00159-00160; 00167, (2019/06/23)
The present invention relates to certain β-lactone compounds that may be useful as inhibitors of bacterial beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising t
A New Mechanism for β-Lactamases: Class D Enzymes Degrade 1β-Methyl Carbapenems through Lactone Formation
Lohans, Christopher T.,van Groesen, Emma,Kumar, Kiran,Tooke, Catherine L.,Spencer, James,Paton, Robert S.,Brem, Jürgen,Schofield, Christopher J.
supporting information, p. 1282 - 1285 (2018/01/27)
β-Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl-enzyme intermediate. We show that class D β-lactamases also degrade clinically used 1β-methyl-substituted carbapenems through the unprecedented formation of a carbapenem-derived β-lactone. β-Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl-enzyme intermediate. The carbapenem-derived lactone products inhibit both serine β-lactamases (particularly class D) and metallo-β-lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required.
On the reactions of the carbapenem, meropenem, in the soluble fraction of the rat kidney
Roy,Hewlins
, p. 185 - 198 (2007/10/03)
When meropenem (I) is incubated with the soluble fraction of rat kidney or its ultrafiltrate the carbapenem disappears at a rate of 50 nmol/min per g of kidney at pH 8.4 and 37°C. In both cases the kinetics are inconsistent with the reaction being enzymic and the product has been shown to be a thiol. The same reaction occurs in similar preparations from the kidney of several other mammalian species. The reaction of meropenem with thiols has been investigated: only those having a vicinal amino group react rapidly. The product of the reaction with cysteine has been characterized as the amide (III) of the latter with meropenoic acid (II), the carboxylic acid formed by the hydrolysis of the β-lactam ring of meropenem. It is postulated that the destruction of meropenem in the soluble fraction of rat kidney occurs by the non-enzymic reaction of the carbapenem with endogenous cysteine or related thiols. There is no evidence that this reaction can occur in vivo but it should be considered in the future design of carbapenems.
