Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 53, Issue 8, Pages 2130-2133Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201308636
Keywords
antibiotic resistance; drug discovery; meropenem; New Delhi metallo-beta-lactamase; NMR spectroscopy
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Funding
- AstraZeneca Internal Postdoctoral program
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Disconnections between invitro responses and those observed in whole cells confound many attempts to design drugs in areas of serious medical need. A method based on 1D H-1 NMR spectroscopy is reported that affords the ability to monitor the hydrolytic decomposition of the carbapenem antibiotic meropenem inside Escherichia coli cells expressing New Delhi metallo--lactamase subclass 1 (NDM-1), an emerging antibiotic-resistance threat. Cell-based NMR studies demonstrated that two known NDM-1 inhibitors, L-captopril and ethylenediaminetetraacetic acid (EDTA), inhibit the hydrolysis of meropenem invivo. NDM-1 activity in cells was also shown to be inhibited by spermine, a porin inhibitor, although in an invitro assay, the influence of spermine on the activity of isolated NDM-1 protein is minimal. This new approach may have generic utility for monitoring reactions involving diffusible metabolites in other complex biological matrices and whole-cell settings, including mammalian cells.
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