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Chemistry. 2018 Jun 7;24(32):8081-8086. doi: 10.1002/chem.201800923. Epub 2018 May 14.

Synthesis of Avibactam Derivatives and Activity on β-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria.

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Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, INSERM, Centre de Recherche des Cordeliers, CRC, 75006, Paris, France.
Laboratoire de Chimie et de Biochimie, Pharmacologiques et Toxicologiques, Université Paris Descartes, UMR 8601, 75005, Paris, France.
CNRS UMR 8601, 75006, Paris, France.
Service de Microbiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
Fonction et Architecture des Assemblages Macromoléculaires, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, 91198, Gif-sur-Yvette cedex, France.


There is a renewed interest for β-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their β-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen-Sharpless cycloaddition reaction is reported. The amoxicillin-DBO combinations were active, indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 μg mL-1 for both species). Mechanistically, β-lactamase inhibition was not sufficient to account for the potentiation of amoxicillin by DBOs. Thus, the latter compounds were investigated as inhibitors of l,d-transpeptidases (Ldts), which are the main peptidoglycan polymerases in mycobacteria. The DBOs acted as slow-binding inhibitors of Ldts by S-carbamoylation indicating that optimization of DBOs for Ldt inhibition is an attractive strategy to obtain drugs selectively active on mycobacteria.


Avibactam; Mycobacterium abscessus; Mycobacterium tuberculosis; l,d-transpeptidases; β-lactamase

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