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.
Chemistry. 2018 Jun 7;24(32):8081-8086. doi: 10.1002/chem.201800923. Epub 2018 May 14.
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 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.
由于结核分枝杆菌和脓肿分枝杆菌的β-内酰胺酶分别被经典（克拉维酸）或新一代（阿维巴坦）抑制剂抑制，因此人们对β-内酰胺类药物治疗感染重新产生了兴趣。在此，报道了一种用于通过霍夫曼-施陶布环加成反应进行功能化的阿维巴坦的叠氮衍生物。阿莫西林-DBO 组合具有活性，表明三唑环与药物渗透兼容（两种物种的最小抑菌浓度均为 16μg/mL）。从机制上讲，β-内酰胺酶抑制不足以解释 DBO 对阿莫西林的增效作用。因此，研究了这些化合物作为 l,d-转肽酶（Ldts）的抑制剂，Ldts 是分枝杆菌中主要的肽聚糖聚合酶。DBO 通过 S-氨甲酰化作用作为 Ldts 的缓慢结合抑制剂，表明优化 DBO 对 Ldt 的抑制作用是获得对分枝杆菌具有选择性活性的药物的一种有吸引力的策略。
