Target‐Based Whole‐Cell Screening by 1H NMR Spectroscopy |
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Authors: | Dr Junhe Ma Qing Cao Dr Sarah M McLeod Keith Ferguson Ning Gao Prof Alexander L Breeze Dr Jun Hu |
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Institution: | 1. Discovery Sciences, AstraZeneca R&D Boston, Waltham, Massachusetts 02451 (USA);2. Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts 02451 (USA);3. Discovery Sciences, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TG (UK);4. Current address: Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT (UK) |
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Abstract: | 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 IC50 of 0.51 μM , 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. |
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Keywords: | drug discovery in vivo methods New Delhi metallo‐β ‐lactamase NMR spectroscopy whole‐cell screening |
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