The Antimicrobial Peptide Thanatin Disrupts the Bacterial Outer Membrane and Inactivates the NDM-1 metallo-β-lactamase

Nat Commun. 2019 Aug 6;10(1):3517. doi: 10.1038/s41467-019-11503-3.

Abstract

New Delhi metallo-β-lactamase-1 (NDM-1) is the most prevalent type of metallo-β-lactamase and hydrolyzes almost all clinically used β-lactam antibiotics. Here we show that the antimicrobial peptide thanatin disrupts the outer membrane of NDM-1-producing bacteria by competitively displacing divalent cations on the outer membrane and inducing the release of lipopolysaccharides. In addition, thanatin inhibits the enzymatic activity of NDM-1 by displacing zinc ions from the active site, and reverses carbapenem resistance in NDM-1-producing bacteria in vitro and in vivo. Thus, thanatin's dual mechanism of action may be useful for combating infections caused by NDM-1-producing pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Antimicrobial Cationic Peptides / pharmacology*
  • Antimicrobial Cationic Peptides / therapeutic use
  • Carbapenems / pharmacology
  • Catalytic Domain / drug effects
  • Cell Wall / drug effects*
  • Disease Models, Animal
  • Escherichia coli / drug effects
  • Escherichia coli / metabolism
  • Escherichia coli Infections / drug therapy
  • Escherichia coli Infections / microbiology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inhibitory Concentration 50
  • Klebsiella Infections / drug therapy
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / metabolism
  • Mice
  • Microbial Sensitivity Tests
  • Zinc / metabolism
  • beta-Lactam Resistance / drug effects*
  • beta-Lactamases / metabolism*

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Carbapenems
  • thanatin
  • beta-Lactamases
  • beta-lactamase NDM-1
  • Zinc