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

Shui Liu,Jiyun Li,Tingting Wang,Jianfeng Wang,Xuming Deng,Zhongjie Liu,Xiaodi Niu,Yang Wang,Shusheng Tang,Yonglin Zhou

doi:10.1038/s41420-018-0029-6

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 Escherichia coli ZC-YN3, an NDM-1-producing E. coli isolate, in in vitro antibacterial activity assays. Magnolol lacked direct antibacterial activity, but compared with meropenem alone, it reduced the MICs of meropenem against E. coli 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.

Highlights

The emergence and dissemination of multidrug-resistant pathogens, especially Gram-negative bacteria that encode extended-spectrum β-lactamases and are resistant to almost all currently available β-lactam antibiotics, is a worldwide public health problem[1, 2]
MBLs are the major targets for developing efficient inhibitors against carbapenem-resistant Enterobacteriaceae[18]
In 2014, King et al identified a fungal natural product, aspergillomarasmine A (AMA), which is as an effective inhibitor of New Delhi metallo-β-lactamase-1 (NDM-1) and VIM-2, through a cellbased screening approach[21]

Summary

Introduction

The emergence and dissemination of multidrug-resistant pathogens, especially Gram-negative bacteria that encode extended-spectrum β-lactamases and are resistant to almost all currently available β-lactam antibiotics, is a worldwide public health problem[1, 2]. Potent carbapenems, such as meropenem and imipenem, were once regarded as the last line of defense against multidrug-resistant Gramnegative bacteria[3] as they are relatively stable in the presence of most bacterial β-lactamases, including extendedspectrum β-lactamases[4]. They were first identified half a century ago[17], many MBLs, such as the Verona integron-

Methods

Results

Conclusion