Target‐Based Whole‐Cell Screening by 1 H NMR Spectroscopy

An NMR‐based approach marries the two traditional screening technologies (phenotypic and target‐based screening) to find compounds inhibiting a specific enzymatic reaction in bacterial cells. Building on a previous study in which it was demonstrated that hydrolytic decomposition of meropenem in livi...

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Veröffentlicht in:Angewandte Chemie International Edition 2015-04, Vol.54 (16), p.4764-4767
Hauptverfasser: Ma, Junhe, Cao, Qing, McLeod, Sarah M., Ferguson, Keith, Gao, Ning, Breeze, Alexander L., Hu, Jun
Format: Artikel
Sprache:eng
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Zusammenfassung:An NMR‐based approach marries the two traditional screening technologies (phenotypic and target‐based screening) to find compounds inhibiting a specific enzymatic reaction in bacterial cells. Building on a previous study in which it was demonstrated that hydrolytic decomposition of meropenem in living Escherichia coli cells carrying New Delhi metallo‐β‐lactamase subclass 1 (NDM‐1) can be monitored in real time by NMR spectroscopy, we designed a cell‐based NMR screening platform. A strong NDM‐1 inhibitor was identified with cellular IC 50 of 0.51 μ M , which is over 300‐fold more potent than captopril, a known NDM‐1 inhibitor. This new screening approach has great potential to be applied to targets in other cell types, such as mammalian cells, and to targets that are only stable or functionally competent in the cellular environment.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201410701