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J Med Chem. 2020 Dec 24;63(24):15802-15820. doi: 10.1021/acs.jmedchem.0c01535. Epub 2020 Dec 11.
The diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of β-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of β-lactam antibiotics against carbapenem-resistant (CRAB), a WHO "critical priority pathogen" producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure-activity relationship, leading to the discovery of a novel DBO, , which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.
二氮杂二环辛烷（DBO）类是一类丝氨酸β-内酰胺酶（SBL）抑制剂，它们使用刚性脲部分作为弹头，与 SBL 活性位点中的活性丝氨酸残基反应。首个同类药物阿维巴坦以及其他几种最近批准的 DBO（如雷利巴坦）或正在临床开发中的 DBO（如那库巴坦和齐德巴坦）不同程度地增强了β-内酰胺类抗生素对携带 A、C 和 D 类 SBL 的碳青霉烯类耐药肠杆菌科（CRE）的活性；然而，这些药物都不能恢复β-内酰胺类抗生素对碳青霉烯类耐药（CRAB）的活性，后者是世界卫生组织“关键优先病原体”，可产生 D 类 OXA 型 SBL。本文描述了化学优化及由此产生的构效关系，最终发现了一种新型 DBO ，它独特地用氟原子取代了羧酰胺，与目前的 DBO 类药物不同，它可以恢复碳青霉烯类药物对 OXA-CRAB 以及携带 SBL 的 CRE 病原体的活性。
