Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors,Journal of Medicinal Chemistry

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Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-04-14 , DOI: 10.1021/acs.jmedchem.2c00213
Cheng Chen ₁ , Peter Oelschlaeger ₂ , Dongmei Wang ₁ , Hao Xu ₃ , Qian Wang ₄ , Cheng Wang ₁ , Aiguo Zhao ₁ , Ke-Wu Yang ₅

Affiliation

Serine/metallo-carbapenemase-coproducing pathogens, often referred to as “superbugs”, are a significant clinical problem. They hydrolyze nearly all available β-lactam antibiotics, especially carbapenems considered as last-resort antibiotics, seriously endangering efficacious antibacterial treatment. Despite the continuous global spread of carbapenem resistance, no dual-action inhibitors are available in therapy. This Perspective is the first systematic investigation of all chemotypes, modes of inhibition, and crystal structures of dual serine/metallo-carbapenemase inhibitors. An overview of the key strategy for designing dual serine/metallo-carbapenemase inhibitors and their mechanism of action is provided, as guiding rules for the development of clinically available dual inhibitors, coadministrated with carbapenems, to overcome the carbapenem resistance issue.

中文翻译：

双丝氨酸/金属碳青霉烯酶抑制剂的结构和机制指导设计

丝氨酸/金属碳青霉烯酶共产病原体，通常被称为“超级细菌”，是一个重要的临床问题。它们水解几乎所有可用的β-内酰胺类抗生素，尤其是被认为是最后的抗生素的碳青霉烯类，严重危及有效的抗菌治疗。尽管碳青霉烯类耐药性在全球范围内持续蔓延，但没有双重作用抑制剂可用于治疗。该观点是对双丝氨酸/金属碳青霉烯酶抑制剂的所有化学类型、抑制模式和晶体结构的首次系统研究。概述了设计丝氨酸/金属碳青霉烯酶双重抑制剂的关键策略及其作用机制，作为开发临床可用双重抑制剂与碳青霉烯类药物共同给药的指导规则，

更新日期：2022-04-14

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