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dc.contributor.authorKondratieva, Alexandra
dc.contributor.authorPalica, Katarzyna
dc.contributor.authorFrøhlich, Christopher
dc.contributor.authorRolfsnes Hovd, Rebekka
dc.contributor.authorLeiros, Hanna-Kirsti S.
dc.contributor.authorErdélyi, Máté
dc.contributor.authorBayer, Annette
dc.date.accessioned2024-01-31T14:07:44Z
dc.date.available2024-01-31T14:07:44Z
dc.date.issued2024-01-10
dc.description.abstractBacterial 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 IC50 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.en_US
dc.identifier.citationKondratieva A, Palica K, Frøhlich CF, Rolfsnes Hovd, Leiros H, Erdélyi M, Bayer A. Fluorinated captopril analogues inhibit metallo-β-lactamases and facilitate structure determination of NDM-1 binding pose. European Journal of Medicinal Chemistry. 2024en_US
dc.identifier.cristinIDFRIDAID 2228221
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttps://hdl.handle.net/10037/32797
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.ispartofKondratieva, A. (2024). Exploring fluorination in MBL inhibitor design. (Doctoral thesis). <a href=https://hdl.handle.net/10037/33756>https://hdl.handle.net/10037/33756</a>
dc.relation.journalEuropean Journal of Medicinal Chemistry
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2024 The Author(s)en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.rightsAttribution 4.0 International (CC BY 4.0)en_US
dc.titleFluorinated captopril analogues inhibit metallo-β-lactamases and facilitate structure determination of NDM-1 binding poseen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's license is described as Attribution 4.0 International (CC BY 4.0)