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

Synthesis of Avibactam Derivatives and Activity on β‐Lactamases and Peptidoglycan Biosynthesis... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Chemistry - A European Journal Wiley

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Publisher
Wiley
Copyright
© 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim
ISSN
0947-6539
eISSN
1521-3765
D.O.I.
10.1002/chem.201800923
Publisher site
See Article on Publisher Site

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.

Journal

Chemistry - A European JournalWiley

Published: Jan 7, 2018

Keywords: ; ; ; ;

References

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