期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 24, 期 32, 页码 8081-8086出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201800923
关键词
Avibactam; L,D-transpeptidases; Mycobacterium abscessus; Mycobacterium tuberculosis; beta-lactamase
资金
- French National Research Agency (grant MycWall) [ANR-17-CE18-0010]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]
- Fondation pour la Recherche Medicale [ECO20160736080]
- Vaincre la Mucoviscidose [RIF2017050244]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE18-0010] Funding Source: Agence Nationale de la Recherche (ANR)
There is a renewed interest for beta-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their beta-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 mu g mL(-1) for both species). Mechanistically, beta-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.
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