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Pterostilbene restores carbapenem susceptibility in New Delhi metallo‐β‐lactamase‐producing isolates by inhibiting the activity of New Delhi metallo‐β‐lactamases
Author(s) -
Liu Shui,
Zhang Jian,
Zhou Yonglin,
Hu Naiyu,
Li Jiyun,
Wang Yang,
Niu Xiaodi,
Deng Xuming,
Wang Jianfeng
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14818
Subject(s) - pterostilbene , klebsiella pneumoniae , microbiology and biotechnology , meropenem , in vivo , antibacterial activity , enzyme , bacteria , in vitro , chemistry , biology , pharmacology , biochemistry , antibiotics , antibiotic resistance , escherichia coli , resveratrol , genetics , gene
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.