Metallo-ß-lactamases inhibitor fisetin attenuates meropenem resistance in NDM-1-producing Escherichia coli.
Eur J Med Chem
; 231: 114108, 2022 Mar 05.
Article
in En
| MEDLINE
| ID: mdl-35101651
ABSTRACT
The prevalence and development of New Delhi metallo-ß-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 = 9.68 µg/mL) through on enzyme activity inhibition screening. Notably, fisetin is a metallo-ß-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 (MICï¼1024 µg/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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Escherichia coli
/
Beta-Lactamase Inhibitors
Type of study:
Risk_factors_studies
Language:
En
Journal:
Eur J Med Chem
Year:
2022
Document type:
Article
Affiliation country:
China