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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.

Author information

1
Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, INSERM, Centre de Recherche des Cordeliers, CRC, 75006, Paris, France.
2
Laboratoire de Chimie et de Biochimie, Pharmacologiques et Toxicologiques, Université Paris Descartes, UMR 8601, 75005, Paris, France.
3
CNRS UMR 8601, 75006, Paris, France.
4
Service de Microbiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
5
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.

Abstract

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.

KEYWORDS:

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

PMID:
29601108
DOI:
10.1002/chem.201800923
[Indexed for MEDLINE]

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