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Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-30 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00407 Allie Y. Chen 1 , Pei W. Thomas 2 , Alesha C. Stewart 2 , Alexander Bergstrom 3 , Zishuo Cheng 3 , Callie Miller 3 , Christopher R. Bethel 4 , Steven H. Marshall 4 , Cy V. Credille 1 , Christopher L. Riley 5 , Richard C. Page 3 , Robert A. Bonomo 4, 6 , Michael W. Crowder 3 , David L. Tierney 3 , Walter Fast 2 , Seth M. Cohen 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-30 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00407 Allie Y. Chen 1 , Pei W. Thomas 2 , Alesha C. Stewart 2 , Alexander Bergstrom 3 , Zishuo Cheng 3 , Callie Miller 3 , Christopher R. Bethel 4 , Steven H. Marshall 4 , Cy V. Credille 1 , Christopher L. Riley 5 , Richard C. Page 3 , Robert A. Bonomo 4, 6 , Michael W. Crowder 3 , David L. Tierney 3 , Walter Fast 2 , Seth M. Cohen 1
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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). By utilization of 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. On the basis of 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 coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.
中文翻译：
二吡啶甲酸衍生物作为新德里金属β-内酰胺酶-1的抑制剂
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-内酰胺类抗生素的有效性。通过利用基于片段的药物发现（FBDD），鉴定出一类新型的NDM-1抑制剂和两种相关的β-内酰胺酶IMP-1和VIM-2。在2,6-二吡啶甲酸（DPA）的基础上，合成了多个文库用于结构-活性关系（SAR）分析。与其他Zn（II）金属酶相比，抑制剂36（IC 50 = 80 nM）被鉴定为对MBL具有高度选择性。虽然DPA显示出螯合NDM-1中金属离子的倾向，但36形成了稳定的NDM-1：Zn（II）：抑制剂三元络合物，如1所示。1 H 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。当与36种（对哺乳动物细胞无毒的浓度）共同给药时，亚胺培南对具有NDM-1的大肠杆菌和肺炎克雷伯菌的临床分离株的最低抑制浓度（MIC）降低至易感水平。
更新日期：2017-08-30
中文翻译：
二吡啶甲酸衍生物作为新德里金属β-内酰胺酶-1的抑制剂
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-内酰胺类抗生素的有效性。通过利用基于片段的药物发现（FBDD），鉴定出一类新型的NDM-1抑制剂和两种相关的β-内酰胺酶IMP-1和VIM-2。在2,6-二吡啶甲酸（DPA）的基础上，合成了多个文库用于结构-活性关系（SAR）分析。与其他Zn（II）金属酶相比，抑制剂36（IC 50 = 80 nM）被鉴定为对MBL具有高度选择性。虽然DPA显示出螯合NDM-1中金属离子的倾向，但36形成了稳定的NDM-1：Zn（II）：抑制剂三元络合物，如1所示。1 H 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。当与36种（对哺乳动物细胞无毒的浓度）共同给药时，亚胺培南对具有NDM-1的大肠杆菌和肺炎克雷伯菌的临床分离株的最低抑制浓度（MIC）降低至易感水平。
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