Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-beta-lactamase-1

作者：Chen Allie Y; Thomas Pei W; Stewart Alesha C; Bergstrom Alexander; Cheng Zishuo; Miller Callie; Bethel Christopher R; Marshal 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^*

来源：Journal of Medicinal Chemistry, 2017, 60(17): 7267-7283.

DOI：10.1021/acs.jmedchem.7b00407

The efficacy of beta-lactam antibiotics is threatened by the emergence and global spread of metallo-beta-lactamase (MBL) mediated resistance, specifically New Delhi metallo-beta-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related beta-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 H-1 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.

• 出版日期2017-9-14