Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1.
Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1.
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DOI：
10.1021/acs.jmedchem.7b00407
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发表时间：
2017-09-14
影响因子：
7.3
通讯作者：
Cohen SM
中科院分区：
文献类型：
--
作者：
Chen AY;Thomas PW;Stewart AC;Bergstrom A;Cheng Z;Miller C;Bethel CR;Marshall SH;Credille CV;Riley CL;Page RC;Bonomo RA;Crowder MW;Tierney DL;Fast W;Cohen SM
金属β-内酰胺酶（MBL）介导的耐药性（特别是新德里金属β-内酰胺酶-1（NDM-1））的出现和全球传播威胁着β-内酰胺抗生素的疗效。利用基于片段的药物发现（FBDD），鉴定了一类新的NDM-1和两种相关β-内酰胺酶IMP-1和Vim-2的抑制剂。以2，6-吡啶二甲酸（DPA）为基础，合成了几种用于构效关系分析的化合物库。抑制剂36（IC 50 = 80 nM）被确定为是高度选择性的MBLs相比，其他锌（II）金属酶。虽然DPA显示出从NDM-1螯合金属离子的倾向，但36形成了稳定的NDM-1：Zn（II）：抑制剂三元复合物，如通过1H NMR、电子顺磁共振（EPR）光谱、平衡透析、固有色氨酸荧光发射和UV-Vis光谱所证明的。当与36（对哺乳动物细胞无毒的浓度）联合给药时，亚胺培南对携带NDM-1的大肠杆菌和肺炎克雷伯菌临床分离株的最低抑制浓度（MIC）降低至敏感水平。
The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase-(MBL) mediated resistance, specifically New Delhi-Metallo-β-lactamase-1 (NDM-1). Utilizing fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. Based on 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-Vis spectroscopy. When co-administered with 36 (at concentrations non-toxic to mammalian cells), the minimum inhibitory concentration (MIC) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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通讯作者：
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