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dc.contributor.authorSkagseth, Susann
dc.contributor.authorAkhter, Sundus
dc.contributor.authorPaulsen, Marianne H
dc.contributor.authorMuhammad, Zeeshan
dc.contributor.authorSamuelsen, Ørjan
dc.contributor.authorLeiros, Hanna-Kirsti S.
dc.contributor.authorBayer, Annette
dc.date.accessioned2018-04-26T16:05:20Z
dc.date.available2018-04-26T16:05:20Z
dc.date.issued2017-04-14
dc.description.abstractBacterial resistance is compromising the use of β-lactam antibiotics including carbapenems. The main resistance mechanism against β-lactams is hydrolysis of the β-lactam ring mediated by serine- or metallo-β-lactamases (MBLs). Although several inhibitors of MBLs have been reported, none has been developed into a clinically useful inhibitor. Mercaptocarboxylic acids are among the most prominent scaffolds reported as MBL inhibitors. In this study, the carboxylate group of mercaptocarboxylic acids was replaced with bioisosteric groups like phosphonate esters, phosphonic acids and NH-tetrazoles. The influence of the replacement on the bioactivity and inhibitor binding was evaluated. A series of bioisosteres of previously reported inhibitors was synthesized and evaluated against the MBLs VIM-2, NDM-1 and GIM- 1. The most active inhibitors combined a mercapto group and a phosphonate ester or acid, with two/three carbon chains connecting a phenyl group. Surprisingly, also compounds containing thioacetate groups instead of thiols showed low IC50 values. High-resolution crystal structures of three inhibitors in complex with VIM-2 revealed hydrophobic interactions for the diethyl groups in the phosphonate ester (inhibitor 2b), the mercapto bridging the two active site zinc ions, and tight stacking of the benzene ring to the inhibitor between Phe62, Tyr67, Arg228 and His263. The inhibitors show reduced enzyme activity in Escherichia coli cells harboring MBL. The obtained results will be useful for further structural guided design of MBL inhibitors.en_US
dc.descriptionAccepted manuscript version, licensed <a href=http://creativecommons.org/licenses/by-nc-nd/4.0/> CC BY-NC-ND 4.0. </a>" . Published version available in <a href=https://doi.org/10.1016/j.ejmech.2017.04.035> European Journal of Medicinal Chemistry. 135:159-173. </a>en_US
dc.identifier.citationSkagseth, S., Akhter, S., Paulsen, M. H., Muhammad, Z., Samuelsen, Ø., Leiros, H. & Bayer, A. (2017). Metallo-β-lactamase inhibitors by bioisosteric replacement: preparation, activity and binding. European Journal of Medicinal Chemistry. 135:159-173. https://doi.org/10.1016/j.ejmech.2017.04.035en_US
dc.identifier.cristinIDFRIDAID 1466591
dc.identifier.doidx.doi.org/10.1016/j.ejmech.2017.04.035
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttps://hdl.handle.net/10037/12626
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalEuropean Journal of Medicinal Chemistry
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRIMEDBIO/213808/NORWAY/Combating Antibiotic Resistance - Development of Inhibitors against Antibiotic Resistance Enzymes//en_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical microbiology: 715en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk mikrobiologi: 715en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk biokjemi: 726en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical biochemistry: 726en_US
dc.subjectCrystal structureen_US
dc.subjectInhibition propertiesen_US
dc.subjectCarboxylate bioisostersen_US
dc.subjectThiolsen_US
dc.subjectMetallo-β-lactamase inhibitorsen_US
dc.titleMetallo-β-lactamase inhibitors by bioisosteric replacement: preparation, activity and bindingen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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