金属-β-内酰胺酶抑制剂的机理研究：强效的酶抑制不需要强锌结合**,ChemMedChem

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金属-β-内酰胺酶抑制剂的机理研究：强效的酶抑制不需要强锌结合**
ChemMedChem ( IF 3.6 ) Pub Date : 2021-02-03 , DOI: 10.1002/cmdc.202100042
Nicola Wade ₁ , Kamaleddin H M E Tehrani ₁ , Nora C Brüchle ₁ , Matthijs J van Haren ₁ , Vida Mashayekhi ₂ , Nathaniel I Martin ₁

Affiliation

金属-β-内酰胺酶 (MBL) 是锌依赖性细菌酶，可灭活几乎所有类别的 β-内酰胺抗生素，包括最后手段碳青霉烯类。目前尚无临床批准的 MBL 抑制剂，为了开发此类药物，有必要了解其抑制机制。在此，我们描述了对科学和专利文献中报道的一组结构不同的 MBL 抑制剂的全面机制研究。具体来说，我们确定了每种抑制剂针对属于 NDM 和 IMP 家族的 MBL 的半最大抑制浓度 (IC _{50 )。}此外，通过使用等温滴定量热法(ITC)评估抑制剂对Zn ²⁺、Ca ²⁺ 和Mg ^{2+ 的结合亲和力。}我们还比较了不同抑制剂使表达高度耐药的 MBL大肠杆菌菌株对美罗培南重新敏感的能力。这些研究揭示了所研究的 MBL 抑制剂在 IC ₅₀值、金属结合能力以及与美罗培南协同作用的能力方面的明显差异。值得注意的是，我们的研究表明，有效的 MBL 抑制以及与美罗培南的协同作用并不明确依赖于抑制剂强烈螯合锌的能力。

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Mechanistic Investigations of Metallo-β-lactamase Inhibitors: Strong Zinc Binding Is Not Required for Potent Enzyme Inhibition**

Metallo-β-lactamases (MBLs) are zinc-dependent bacterial enzymes that inactivate essentially all classes of β-lactam antibiotics including last-resort carbapenems. At present there are no clinically approved MBL inhibitors, and in order to develop such agents it is essential to understand their inhibitory mechanisms. Herein, we describe a comprehensive mechanistic study of a panel of structurally distinct MBL inhibitors reported in both the scientific and patent literature. Specifically, we determined the half-maximal inhibitory concentration (IC₅₀) for each inhibitor against MBLs belonging to the NDM and IMP families. In addition, the binding affinities of the inhibitors for Zn²⁺, Ca²⁺ and Mg²⁺were assessed by using isothermal titration calorimetry (ITC). We also compared the ability of the different inhibitors to resensitize a highly resistant MBL-expressing Escherichia coli strain to meropenem. These investigations reveal clear differences between the MBL inhibitors studied in terms of their IC₅₀ value, metal binding ability, and capacity to synergize with meropenem. Notably, our studies demonstrate that potent MBL inhibition and synergy with meropenem are not explicitly dependent on the capacity of an inhibitor to strongly chelate zinc.

更新日期：2021-02-03

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