Inhibitor discovery of full-length New Delhi metallo-β-lactamase-1 (NDM-1)

PLoS One. 2013 May 13;8(5):e62955. doi: 10.1371/journal.pone.0062955. Print 2013.

Abstract

New Delhi metallo-β-lactmase-1 (NDM-1) has recently attracted extensive attention for its biological activities to catalyze the hydrolysis of almost all of β-lactam antibiotics. To study the catalytic property of NDM-1, the steady-kinetic parameters of NDM-1 toward several kinds of β-lactam antibiotics have been detected. It could effectively hydrolyze most β-lactams (k cat/K m ratios between 0.03 to 1.28 µmol⁻¹.s⁻¹), except aztreonam. We also found that thiophene-carboxylic acid derivatives could inhibit NDM-1 and have shown synergistic antibacterial activity in combination with meropenem. Flexible docking and quantum mechanics (QM) study revealed electrostatic interactions between the sulfur atom of thiophene-carboxylic acid derivatives and the zinc ion of NDM-1, along with hydrogen bond between inhibitor and His189 of NDM-1. The interaction models proposed here can be used in rational design of NDM-1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Aztreonam / chemistry*
  • Aztreonam / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Drug Synergism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / chemistry
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology*
  • Hydrolysis
  • Kinetics
  • Meropenem
  • Molecular Docking Simulation
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Thienamycins / chemistry*
  • Thienamycins / pharmacology
  • beta-Lactam Resistance / drug effects
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / chemistry
  • beta-Lactamases / genetics
  • beta-Lactams / chemistry*
  • beta-Lactams / pharmacology

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Recombinant Fusion Proteins
  • Thienamycins
  • beta-Lactamase Inhibitors
  • beta-Lactams
  • beta-Lactamases
  • beta-lactamase NDM-1
  • Meropenem
  • Aztreonam

Grants and funding

This work was supported by the Open Project Program of State Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences (No.Y052010040) and the Fundamental Research Funds for the Central Universities of China (No. JKZ2009007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.