Format

Send to

Choose Destination
Br J Pharmacol. 2019 Aug 2. doi: 10.1111/bph.14818. [Epub ahead of print]

Pterostilbene restores carbapenem susceptibility in NDM-producing isolates via inhibiting the activity of NDM enzymes.

Author information

1
Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.
2
College of Animal Sciences, Jilin University, Changchun, China.
3
Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
4
College of Food Science and Engineering, Jilin University, Changchun, China.

Abstract

BACKGROUND AND PURPOSE:

Bacteria producing New Delhi metallo-β-lactamase-1 (NDM-1) are an increasing clinical threat. NDM-1 can inactivate almost all β-lactams and is not sensitive to any existing β-lactamase inhibitors. To identify effective inhibitors of the NDM-1 enzyme and clarify the mechanism of action, a "lead compound" for developing more potent NDM-1 inhibitors needs to be provided.

EXPERIMENTAL APPROACH:

Natural compounds were tested by enzyme inhibition screening to find potential inhibitors. MIC assays, growth curve assays and time-kill assays were conducted to evaluate the in vitro antibacterial activity of pterostilbene and the combination of pterostilbene and meropenem. A murine thigh model and a mouse pneumonia model were used to evaluate the in vivo efficacy of combined therapy. Molecular modelling and a mutational analysis were used to clarify the mechanism of action.

KEY RESULTS:

Pterostilbene significantly inhibited NDM-1 hydrolysis activity in enzyme inhibition screening assays and effectively restored the effectiveness of meropenem in vitro with NDM-expressing isolates in antibacterial activity assays. In addition, the combined therapy effectively reduced the bacterial burden in a murine thigh model and protected mice from pneumonia caused by Klebsiella pneumoniae. By means of molecular dynamics simulation, we observed that pterostilbene localized to the catalytic pocket of NDM-1, hindering substrate binding to NDM-1 and reducing NDM-1 activity.

CONCLUSIONS AND IMPLICATIONS:

These findings indicated that pterostilbene combined with meropenem may offer a new safe and potential "lead compound" for the further development of NDM-1 inhibitors.

KEYWORDS:

Enterobacteriaceae; NDM-1; carbapenemase; inhibitor; pterostilbene

PMID:
31376166
DOI:
10.1111/bph.14818

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center