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 Enzymes of Mycobacteria
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DOI：
10.1002/chem.201800923
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发表时间：
2018-06-07
影响因子：
4.3
通讯作者：
Hugonnet, Jean-Emmanuel
中科院分区：
文献类型：
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作者：
Edoo, Zainab;Iannazzo, Laura;Hugonnet, Jean-Emmanuel
治疗结核分枝杆菌和脓肿分支杆菌感染的β-内酰胺类药物重新引起人们的兴趣，因为它们的β-内酰胺酶分别被经典的(克拉维酸)或新一代(阿维巴坦)抑制剂抑制。本文报道了通过惠氏-夏普莱斯环加成反应获得阿维巴坦的双氮双环辛烷(DBO)支架的叠氮衍生物。阿莫西林-DBO组合是有效的，表明三唑环与药物渗透相容(两种药物的最小抑菌浓度均为16微克·毫升)。从机理上讲，β-内酰胺酶抑制不足以解释DBO对阿莫西林的增强作用。因此，后一类化合物被研究为L的抑制剂，D-转肽酶是分枝杆菌中主要的肽聚糖聚合酶。通过S-氨甲酰化反应，DBO作为LDT的慢结合抑制剂，表明优化DBO对LDT的抑制是获得选择性抑制分枝杆菌药物的一种有吸引力的策略。
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.