Chen Allie Y, Thomas Pei W, Stewart Alesha C, Bergstrom Alexander, Cheng Zishuo, Miller Callie, Bethel Christopher R, Marshall Steven H, Credille Cy V, Riley Christopher L, Page Richard C, Bonomo Robert A, Crowder Michael W, Tierney David L, Fast Walter, Cohen Seth M
Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093, United States.
Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy, University of Texas , Austin, Texas 78712, United States.
J Med Chem. 2017 Sep 14;60(17):7267-7283. doi: 10.1021/acs.jmedchem.7b00407. Epub 2017 Aug 30.
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 (IC = 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 H 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.
金属β-内酰胺酶（MBL）介导的耐药性的出现和全球传播，尤其是新德里金属β-内酰胺酶-1（NDM-1），对β-内酰胺类抗生素的疗效构成了威胁。通过基于片段的药物发现（FBDD），鉴定出了一类针对NDM-1以及两种相关β-内酰胺酶IMP-1和VIM-2的新型抑制剂。基于2,6-二吡啶甲酸（DPA），合成了几个文库用于构效关系（SAR）分析。与其他锌（II）金属酶相比，抑制剂36（IC = 80 nM）对MBL具有高度选择性。虽然DPA表现出从NDM-1螯合金属离子的倾向，但36形成了稳定的NDM-1:锌（II）:抑制剂三元复合物，这通过1H NMR、电子顺磁共振（EPR）光谱、平衡透析、色氨酸固有荧光发射和紫外可见光谱得到了证明。当与36共同给药（浓度对哺乳动物细胞无毒）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菌浓度（MICs）降低到了敏感水平。
