Metallo-13-lactamases inhibitor fisetin attenuates meropenem resistance in NDM-1-producing Escherichia coli

The prevalence and development of New Delhi metallo-13-lactamase-1 (NDM-1) have led to increases in bacterial resistance to the majority of clinically used antibiotics, including carbapenems. This study attempts to identify a novel inhibitor of NDM-1 for resistant bacteria infection. Herein, we found that fisetin, as an agent, distinctly inhibits the activity of NDM-1 (IC50 1/4 9.68 mu g/mL) through on enzyme activity inhibition screening. Notably, fisetin is a metallo-13-lactamases inhibitor without the ability to chelate zinc ions, as well as with a significantly inhibitory effect on NDM-9, VIM-1, IMP-1 and KPC-2. The combination of fisetin with meropenem could attenuate meropenem resistance in NDM-1-positive Escherichia coli. The MIC values of combined treatment were lower than those found for meropenem or fisetin alone (FICI from 0.25 +/- 0.00 to 0.38 +/- 0.00) although fisetin lacks antibacterial activities (MIC> 1024 mu g/mL). Furthermore, fisetin combined with meropenem could kill all tested bacteria no more than 3 h in vitro and this synergistic effect could also be observed in vivo. Molecular dynamics simulations revealed that fisetin successfully inhibit the hydrolytic activity of NDM-1. Additionally, the mutation of NDM-1 resulted in a decreased inhibition of NDM-1 activity by fisetin compared with the WT protein. Finally, our results indicate that fisetin is an effective NDM-1 inhibitor, which suggests the combination of this compound with meropenem is a promising strategy for carbapenem-resistant bacterial infection. (c) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

This study identifies fisetin as an effective inhibitor of NDM-1, reducing bacterial resistance to antibiotics. Combining fisetin with meropenem significantly attenuates resistance and shows synergistic effects in vitro and in vivo. Molecular simulations reveal the mechanism of fisetin's inhibitory activity on NDM-1. Fisetin represents a promising strategy for combating carbapenem-resistant bacterial infections.