Pterostilbene restores carbapenem susceptibility in New Delhi metallo‐β‐lactamase‐producing isolates by inhibiting the activity of New Delhi metallo‐β‐lactamases

Autor:	Yang Wang, Jian Zhang, Naiyu Hu, Yonglin Zhou, Jianfeng Wang, Shui Liu, Jiyun Li, Xuming Deng, Xiaodi Niu
Rok vydání:	2019
Předmět:	Models Molecular 0301 basic medicine Carbapenem Pterostilbene Klebsiella pneumoniae Microbial Sensitivity Tests Meropenem beta-Lactamases Microbiology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Stilbenes Escherichia coli medicine Animals Enzyme Inhibitors Pharmacology chemistry.chemical_classification Mice Inbred BALB C Molecular Structure biology Chemistry biology.organism_classification Research Papers Anti-Bacterial Agents 030104 developmental biology Enzyme Carbapenems Mechanism of action Female medicine.symptom Antibacterial activity 030217 neurology & neurosurgery medicine.drug
Zdroj:	Br J Pharmacol
ISSN:	1476-5381 0007-1188
Popis:	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 https://academic.oup.com/jac/article-abstract/54/6/1085/856174 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 https://academic.oup.com/jac/article-abstract/54/6/1085/856174 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a95850495f04ae8016644356a3a9cff4 https://doi.org/10.1111/bph.14818 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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