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dc.date.accessioned2020-08-07T18:35:22Z
dc.date.available2020-08-07T18:35:22Z
dc.date.created2020-03-26T12:53:29Z
dc.date.issued2020
dc.identifier.citationSamuelsen, Ørjan Åstrand, Ove Alexander Høgmoen Frøhlich, Christopher Heikal, Adam Skagseth, Susann Carlsen, Trine Josefine Olsen Leiros, Hanna-Kirsti S. Bayer, Annette Schnaars, Christian Kildahl-andersen, Geir Lauksund, Silje Finke, Sarah Huber, Sandra Gjøen, Tor Andresen, Adriana Magalhaes Santos Økstad, Ole Andreas Rongved, Pål . ZN148 Is a Modular Synthetic Metallo-beta-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo. Antimicrobial Agents and Chemotherapy. 2020
dc.identifier.urihttp://hdl.handle.net/10852/78208
dc.description.abstractCarbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.en_US
dc.languageEN
dc.publisherAmerican Society for Microbiology
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleZN148 Is a Modular Synthetic Metallo-beta-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivoen_US
dc.typeJournal articleen_US
dc.creator.authorSamuelsen, Ørjan
dc.creator.authorÅstrand, Ove Alexander Høgmoen
dc.creator.authorFrøhlich, Christopher
dc.creator.authorHeikal, Adam
dc.creator.authorSkagseth, Susann
dc.creator.authorCarlsen, Trine Josefine Olsen
dc.creator.authorLeiros, Hanna-Kirsti S.
dc.creator.authorBayer, Annette
dc.creator.authorSchnaars, Christian
dc.creator.authorKildahl-andersen, Geir
dc.creator.authorLauksund, Silje
dc.creator.authorFinke, Sarah
dc.creator.authorHuber, Sandra
dc.creator.authorGjøen, Tor
dc.creator.authorAndresen, Adriana Magalhaes Santos
dc.creator.authorØkstad, Ole Andreas
dc.creator.authorRongved, Pål
cristin.unitcode185,15,23,20
cristin.unitnameSeksjon for farmasøytisk kjemi
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode2
dc.identifier.cristin1803695
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Antimicrobial Agents and Chemotherapy&rft.volume=&rft.spage=&rft.date=2020
dc.identifier.jtitleAntimicrobial Agents and Chemotherapy
dc.identifier.volume64
dc.identifier.issue6
dc.identifier.doihttps://doi.org/10.1128/AAC.02415-19
dc.identifier.urnURN:NBN:no-81304
dc.type.documentTidsskriftartikkelen_US
dc.type.peerreviewedPeer reviewed
dc.source.issn0066-4804
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/78208/1/2020_AAC%25282020%2529e02415-19.full.pdf
dc.type.versionPublishedVersion


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