Shui Liu1, Jian Zhang1, Yonglin Zhou1, Naiyu Hu2, Jiyun Li3, Yang Wang3, Xiaodi Niu4, Xuming Deng1, Jianfeng Wang1. 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.
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 mousepneumonia 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.
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