Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7

ACS Infect Dis. 2018 Feb 9;4(2):135-145. doi: 10.1021/acsinfecdis.7b00106. Epub 2017 Nov 9.

Abstract

Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, 1H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.

Keywords: IMP-7; NDM-1; VIM-2; antibiotic resistance; aspergillomarasmine A; metallo-β-lactamase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / chemistry
  • Aspartic Acid / pharmacology
  • Biological Products / chemistry
  • Biological Products / pharmacology
  • Cobalt / chemistry
  • Enzyme Activation / drug effects
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Zinc / chemistry
  • beta-Lactamase Inhibitors / chemistry
  • beta-Lactamase Inhibitors / pharmacology
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism

Substances

  • Biological Products
  • beta-Lactamase Inhibitors
  • Aspartic Acid
  • aspergillomarasmine A
  • Cobalt
  • beta-lactamase bla(vim-2)
  • beta-Lactamases
  • beta-lactamase NDM-1
  • Zinc