Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1.
J Med Chem, 2017/09/14;60(17):7267-7283.
Chen AY[1], Thomas PW[2], Stewart AC[2], Bergstrom A[3], Cheng Z[3], Miller C[3], Bethel CR[4], Marshall SH[4], Credille CV[1], Riley CL[5], Page RC[3], Bonomo RA[4, 6], Crowder MW[3], Tierney DL[3], Fast W[2], Cohen SM[1]
Affiliations
PMID: 28809565DOI: 10.1021/acs.jmedchem.7b00407
Impact factor: 8.039
Abstract
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.
MeSH terms
Anti-Bacterial Agents; Escherichia coli; Escherichia coli Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Picolinic Acids; Structure-Activity Relationship; beta-Lactamase Inhibitors; beta-Lactamases
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