Fluorinated captopril analogues inhibit metallo-β-lactamases and facilitate structure determination of NDM-1 binding pose.

Autor: Kondratieva A; Department of Chemistry, UiT The Arctic University of Norway, NO-9037, Tromsø, Norway., Palica K; Department of Chemistry - BMC, Organic Chemistry, Uppsala University, 752 37, Uppsala, Sweden., Frøhlich C; Department of Pharmacy, UiT The Arctic University of Norway, NO-9037, Tromsø, Norway., Hovd RR; AdjuTec Pharma, NO-0165 Oslo, Norway., Leiros HS; Department of Chemistry, UiT The Arctic University of Norway, NO-9037, Tromsø, Norway., Erdelyi M; Department of Chemistry - BMC, Organic Chemistry, Uppsala University, 752 37, Uppsala, Sweden., Bayer A; Department of Chemistry, UiT The Arctic University of Norway, NO-9037, Tromsø, Norway. Electronic address: annette.bayer@uit.no.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Feb 15; Vol. 266, pp. 116140. Date of Electronic Publication: 2024 Jan 10.
DOI: 10.1016/j.ejmech.2024.116140
Abstrakt: Bacterial resistance to the majority of clinically used β-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-β-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding. The new compounds showed activity comparable to the non-fluorinated inhibitors against the New Delhi Metallo-β-lactamase-1 (NDM-1). The most active compound, a derivative of D-captopril, exhibited an IC 50 value of 0.3 μM. Several compounds demonstrated synergistic effects, restoring the effect of meropenem and reducing the minimum inhibitory concentration (MIC) values in NDM-1 (up to 64-fold), VIM-2 (up to 8-fold) and IMP-26 (up to 8-fold) harbouring Escherichia coli. NMR spectroscopy and molecular docking of one representative inhibitor determined the binding pose in NDM-1, demonstrating that fluorinated analogues of inhibitors are a valuable tool for structural studies of MBL-inhibitor complexes.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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