Abstract
The emergence and spread of carbapenemase in Gram-negative pathogens poses an enormous threat to global public health. New Delhi metallo-β-lactamase-1 (NDM-1) inactivates nearly every class of β-lactam antibiotics, including carbapenem; however, there is no clinically useful NDM-1 inhibitor. Embelin, an important ingredient in traditional herbal medicine, has anti-tumor effects. The current study is the first to discover and examine the inhibitory activity of embelin against β-lactamase NDM-1. The IC50 of embelin was 2.1 ± 0.2 μM when tested against NDM-1 carbapenemase. Most regions of the embelin molecule were buried within NDM-1’s active site, and the hydroxyl group of embelin interacted directly with the metal ion Zn2+, as shown by molecular dynamic simulation. Systematic analysis of the antibacterial activities of embelin and antibiotics demonstrated that embelin restored meropenem activity against a panel of NDM-positive pathogens, such as Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Based on these results, embelin could be a promising carbapenem adjuvant candidate against NDM-1-producing bacterial strains.
Highlights
Carbapenems are antibiotics that are used for severe and difficult-to-treat infections caused by Gram-negative bacteria
An enzyme activity-based screening, using our in-house collection of natural product extracts and chemicals was initiated in order to find a new New Delhi metallo-β-lactamase 1 (NDM-1) inhibitor
Dose-dependent analyses further revealed that embelin inhibited NDM-1 at an IC50 value of 2.1 ± 0.2 μM and Ki value of 0.19 ± 0.02 μM when meropenem was the substrate (Figures 1B,C)
Summary
Carbapenems are antibiotics that are used for severe and difficult-to-treat infections caused by Gram-negative bacteria. They have broad spectrum antibacterial activity and are stable in the presence of most β-lactamases (Nordmann et al, 2011). The emergence and spread of carbapenem-resistant Gram-negative pathogens pose an enormous threat to global public health (Laxminarayan et al, 2013). The acquisition of metallo-β-lactamases (MBLs), such as NDM-1, is one of the ways that Gram-negative pathogens become resistant to carbapenems, threatening the usefulness of penicillin, cephalosporin and carbapenem when treating these infections (King and Strynadka, 2013). New Delhi metallo-β-lactamase 1 (NDM-1) is a relatively recent and emerging concern among the heterogeneous group of carbapenemases.
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