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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Antimicrobial Cationic Peptides / pharmacology*
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Antimicrobial Cationic Peptides / therapeutic use
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Carbapenems / pharmacology
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Catalytic Domain / drug effects
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Cell Wall / drug effects*
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Disease Models, Animal
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Escherichia coli / drug effects
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Escherichia coli / metabolism
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Escherichia coli Infections / drug therapy
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Escherichia coli Infections / microbiology
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Human Umbilical Vein Endothelial Cells
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Humans
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Inhibitory Concentration 50
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Klebsiella Infections / drug therapy
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Klebsiella Infections / microbiology
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Klebsiella pneumoniae / drug effects
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Klebsiella pneumoniae / metabolism
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Mice
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Microbial Sensitivity Tests
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Zinc / metabolism
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beta-Lactam Resistance / drug effects*
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beta-Lactamases / metabolism*
Substances
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Anti-Bacterial Agents
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Antimicrobial Cationic Peptides
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Carbapenems
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thanatin
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beta-Lactamases
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beta-lactamase NDM-1
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Zinc