dc.date.accessioned | 2020-08-07T18:35:22Z | |
dc.date.available | 2020-08-07T18:35:22Z | |
dc.date.created | 2020-03-26T12:53:29Z | |
dc.date.issued | 2020 | |
dc.identifier.citation | Samuelsen, 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.uri | http://hdl.handle.net/10852/78208 | |
dc.description.abstract | Carbapenem-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.language | EN | |
dc.publisher | American Society for Microbiology | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | ZN148 Is a Modular Synthetic Metallo-beta-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo | en_US |
dc.type | Journal article | en_US |
dc.creator.author | Samuelsen, Ørjan | |
dc.creator.author | Åstrand, Ove Alexander Høgmoen | |
dc.creator.author | Frøhlich, Christopher | |
dc.creator.author | Heikal, Adam | |
dc.creator.author | Skagseth, Susann | |
dc.creator.author | Carlsen, Trine Josefine Olsen | |
dc.creator.author | Leiros, Hanna-Kirsti S. | |
dc.creator.author | Bayer, Annette | |
dc.creator.author | Schnaars, Christian | |
dc.creator.author | Kildahl-andersen, Geir | |
dc.creator.author | Lauksund, Silje | |
dc.creator.author | Finke, Sarah | |
dc.creator.author | Huber, Sandra | |
dc.creator.author | Gjøen, Tor | |
dc.creator.author | Andresen, Adriana Magalhaes Santos | |
dc.creator.author | Økstad, Ole Andreas | |
dc.creator.author | Rongved, Pål | |
cristin.unitcode | 185,15,23,20 | |
cristin.unitname | Seksjon for farmasøytisk kjemi | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1803695 | |
dc.identifier.bibliographiccitation | info: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.jtitle | Antimicrobial Agents and Chemotherapy | |
dc.identifier.volume | 64 | |
dc.identifier.issue | 6 | |
dc.identifier.doi | https://doi.org/10.1128/AAC.02415-19 | |
dc.identifier.urn | URN:NBN:no-81304 | |
dc.type.document | Tidsskriftartikkel | en_US |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 0066-4804 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/78208/1/2020_AAC%25282020%2529e02415-19.full.pdf | |
dc.type.version | PublishedVersion | |