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

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.