Université de Paris, UMR CNRS 8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, 45 rue des Saints-Péres, F-75006 Paris, France.
INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC), F-75006 Paris, France.
J Med Chem. 2020 May 28;63(10):5257-5273. doi: 10.1021/acs.jmedchem.9b02125. Epub 2020 May 14.
Second-generation β-lactamase inhibitors containing a diazabicyclooctane (DBO) scaffold restore the activity of β-lactams against pathogenic bacteria, including those producing class A, C, and D enzymes that are not susceptible to first-generation inhibitors containing a β-lactam ring. Here, we report optimization of a synthetic route to access triazole-containing DBOs and biological evaluation of a series of 17 compounds for inhibition of five β-lactamases representative of enzymes found in pathogenic Gram-negative bacteria. A strong correlation (Spearman coefficient of 0.87; = 4.7 × 10) was observed between the inhibition efficacy of purified β-lactamases and the potentiation of β-lactam antibacterial activity, indicating that DBO functionalization did not impair penetration. In comparison to reference DBOs, avibactam and relebactam, our compounds displayed reduced efficacy, likely due to the absence of hydrogen bonding with a conserved asparagine residue at position 132. This was partially compensated for by additional interactions involving certain triazole substituents.
含二氮杂二环辛烷（DBO）支架的第二代β-内酰胺酶抑制剂恢复了β-内酰胺类药物对包括产生对第一代含β-内酰胺环的抑制剂不敏感的 A、C 和 D 类酶的致病性细菌的活性。在这里，我们报告了一种合成方法的优化，以获得含三唑的 DBO，并对一系列 17 种化合物进行了抑制五种β-内酰胺酶的生物学评价，这些酶代表了致病性革兰氏阴性菌中发现的酶。纯化的β-内酰胺酶的抑制效果与β-内酰胺类抗生素抗菌活性的增强之间存在很强的相关性（Spearman 系数为 0.87； = 4.7×10），这表明 DBO 的功能化没有损害渗透。与参比 DBO 阿维巴坦和雷利巴坦相比，我们的化合物显示出降低的功效，这可能是由于缺乏与位置 132 处保守天冬酰胺残基的氢键相互作用。这部分被某些三唑取代基的额外相互作用所补偿。
