Due to the rapid proliferation of antibiotic-resistant pathogenic bacteria, known as carbapenem-resistant enterobacteriaceae, the efficacy of β-lactam antibiotics is threatened. β-lactam antibiotics constitute over 50% of the available antibiotic arsenal. Recent efforts have been focused on developing inhibitors to these enzymes. In an effort to understand the mechanism of inhibition(s) of four FDA-approved thiol-containing drugs that were previously reported to be inhibitors of New Delhi metallo-β-lactamase (NDM-1), various biochemical and spectroscopic techniques were used. Isothermal titration calorimetry demonstrated the binding affinity to NDM-1 corresponds to the reported IC₅₀ values of the inhibitors. Equilibrium dialyses and metal analyses demonstrated that all of these inhibitors formed ternary complexes with ZnZn-NDM-1. Spectroscopic studies on CoCo-NDM-1 revealed two distinct binding modes for the thiol-containing compounds. These findings validate the need to further investigate the mechanism of inhibition of MBL inhibitors. Further research to identify inhibition capabilities beyond reported IC₅₀ values is necessary for understanding the binding modes of these identified compounds and to provide the necessary foundation for developing clinically relevant MBL inhibitors.

中文翻译：

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发现几种含硫醇药物的 NDM-1 抑制机制的综合生物物理方法。

由于耐碳青霉烯肠杆菌科细菌耐药病原菌的快速增殖，β-内酰胺类抗生素的疗效受到威胁。β-内酰胺类抗生素占可用抗生素库的 50% 以上。最近的努力集中在开发这些酶的抑制剂上。为了了解四种 FDA 批准的含硫醇药物的抑制机制，这些药物以前被报道为新德里金属-β-内酰胺酶 (NDM-1) 的抑制剂，使用了各种生化和光谱技术。等温滴定量热法证明对 NDM-1 的结合亲和力对应于报告的 IC ₅₀抑制剂的值。平衡透析和金属分析表明，所有这些抑制剂都与 ZnZn-NDM-1 形成三元复合物。CoCo-NDM-1 的光谱研究揭示了含硫醇化合物的两种不同的结合模式。这些发现证实了进一步研究 MBL 抑制剂抑制机制的必要性。进一步研究以确定超出报告的 IC ₅₀值的抑制能力对于理解这些已鉴定化合物的结合模式是必要的，并为开发临床相关的 MBL 抑制剂提供必要的基础。