Resistance to β‐lactam antibacterials is commonly associated with the production of the serine β‐lactamases (SBLs) and/or metallo‐β‐lactamases (MBLs). Although clinically useful inhibitors for the SBLs have been developed, no equivalent inhibitors are available for the MBLs, which can hydrolyze almost all β‐lactam antibiotics, including the so‐called “last resort” carbapenems. It is still a challenging task to develop a clinically useful inhibitor that should be broad‐spectrum targeting multiple clinically relevant MBL enzymes that differ in their active site features. This review provides a detailed description of interaction modes of substrates and small‐molecule inhibitors with various MBL enzymes and highlights the importance of metal‐ and “anchor residue”‐binding features to achieve broad‐spectrum MBL inhibition. Recently emerging active site interference strategies include metal ion deprivation, metal ion replacement, and cysteine modification as challenging, but worth experimenting directions for inhibitor development. The metalloenzyme selectivity, metal‐binding pharmacophore, and cellular permeability and accumulation should be properly considered in the further development of clinically useful inhibitors to combat MBL‐mediated antibacterial resistance.

中文翻译：

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针对金属-β-内酰胺酶介导的抗菌耐药性的原理和当前策略。

对 β-内酰胺类抗菌药物的耐药性通常与丝氨酸 β-内酰胺酶 (SBL) 和/或金属-β-内酰胺酶 (MBL) 的产生有关。尽管已经开发出临床上有用的 SBLs 抑制剂，但 MBLs 没有等效的抑制剂，它可以水解几乎所有的 β-内酰胺类抗生素，包括所谓的“最后手段”碳青霉烯类。开发一种临床上有用的抑制剂仍然是一项具有挑战性的任务，该抑制剂应该是广谱靶向多种活性位点特征不同的临床相关 MBL 酶。这篇综述详细描述了底物和小分子抑制剂与各种 MBL 酶的相互作用模式，并强调了金属和“锚定残基”结合特征对实现广谱 MBL 抑制的重要性。最近出现的活性位点干扰策略包括金属离子剥夺、金属离子置换和半胱氨酸修饰，这些策略具有挑战性，但值得探索抑制剂开发的方向。在进一步开发临床有用的抑制剂以对抗 MBL 介导的抗菌耐药性时，应适当考虑金属酶的选择性、金属结合药效团以及细胞渗透性和积累。