The antimicrobial peptide thanatin disrupts the bacterial outer membrane and inactivates the NDM-1 metallo-β-lactamase

• Published in: Nature communications Vol. 10; no. 1; pp. 3517 - 11
• Main Authors: Ma, Bo, Fang, Chao, Lu, Linshan, Wang, Mingzhi, Xue, Xiaoyan, Zhou, Ying, Li, Mingkai, Hu, Yue, Luo, Xiaoxing, Hou, Zheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/34; 14/63; 147/135; 38/22; 38/44; 38/77; 42; 631/326/22/1290; 631/326/421; 631/45/607; 64/60; 692/699/255/1318; 82/1; 82/16; 82/58; 82/80; 82/83; Amides; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial Cationic Peptides - therapeutic use; Antimicrobial peptides; Bacteria; beta-Lactam Resistance - drug effects; beta-Lactamases - metabolism; Carbapenems - pharmacology; Catalytic Domain - drug effects; Cations; Cell Wall - drug effects; Disease Models, Animal; Divalent cations; Enzymatic activity; Escherichia coli - drug effects; Escherichia coli - metabolism; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Human Umbilical Vein Endothelial Cells; Humanities and Social Sciences; Humans; Inhibitory Concentration 50; Klebsiella Infections - drug therapy; Klebsiella Infections - microbiology; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - metabolism; Lipopolysaccharides; Metallo-β-lactamase; Metallography; Mice; Microbial Sensitivity Tests; multidisciplinary; Peptides; Science; Science (multidisciplinary); Zinc; Zinc - metabolism; β-Lactam antibiotics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11503-3

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. The NDM-1 metallo-β-lactamase confers resistance to β-lactam antibiotics. Here, the authors show that the antimicrobial peptide thanatin is active against NDM-1-producing bacteria through a dual mechanism of action consisting of disruption of outer membrane integrity and inhibition of the NDM-1 enzymatic activity.