Magnolol restores the activity of meropenem against NDM-1-producing Escherichia coli by inhibiting the activity of metallo-beta-lactamase

Abstract

The emergence of plasmid-mediated New Delhi metallo-β-lactamase-1 (NDM-1) in carbapenem-resistant Gram-negative pathogens is an increasing clinical threat. Here we report the discovery of an NDM-1 inhibitor, magnolol, through enzyme inhibition screening. We showed that magnolol significantly inhibited NDM enzyme activity (IC₅₀ = 6.47 µg/mL), and it restored the activity of meropenem against <i>Escherichia coli</i> ZC-YN3, an NDM-1-producing <i>E. coli</i> isolate, in in vitro antibacterial activity assays. Magnolol lacked direct antibacterial activity, but compared with meropenem alone, it reduced the MICs of meropenem against <i>E. coli</i> ZC-YN3 by 4-fold and killed almost all the bacteria within 3 h. Molecular modeling and a mutational analysis demonstrated that magnolol binds directly to the catalytic pocket (residues 110 to 200) of NDM-1, thereby blocking the binding of the substrate to NDM-1 and leading to its inactivation. Our results demonstrate that the combination of magnolol and meropenem may have the potential to treat infections caused by NDM-1-positive, carbapenem-resistant Gram-negative pathogens.