A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases

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dc.citation.titleNature Communicationses
dc.citation.volume8es
dc.creatorLisa, María Natalia
dc.creatorPalacios, Antonela R.
dc.creatorAitha, Mahesh
dc.creatorGonzález, Mariano M.
dc.creatorMoreno, Diego M.
dc.creatorCrowder, Michael W.
dc.creatorBonomo, Robert A.
dc.creatorSpencer, James
dc.creatorTierney, David L.
dc.creatorLlarrull, Leticia Irene
dc.creatorVila, Alejandro J.
dc.date.accessioned2021-03-04T19:09:06Z
dc.date.available2021-03-04T19:09:06Z
dc.date.issued2017-09-14
dc.descriptionCarbapenem-resistant Enterobacteriaceae threaten human health, since carbapenems are last resort drugs for infections by such organisms. Metallo-β-lactamases (MβLs) are the main mechanism of resistance against carbapenems. Clinically approved inhibitors of MBLs are currently unavailable as design has been limited by the incomplete knowledge of their mechanism. Here, we report a biochemical and biophysical study of carbapenem hydrolysis by the B1 enzymes NDM-1 and BcII in the bi-Zn(II) form, the mono-Zn(II) B2 Sfh-I and the mono-Zn(II) B3 GOB-18. These MβLs hydrolyse carbapenems via a similar mechanism, with accumulation of the same anionic intermediates. We characterize the Michaelis complex formed by mono-Zn(II) enzymes, and we identify all intermediate species, enabling us to propose a chemical mechanism for mono and binuclear MβLs. This common mechanism open avenues for rationally designed inhibitors of all MβLs, notwithstanding the profound differences between these enzymes’ active site structure, β-lactam specificity and metal content.es
dc.description.filFil: Lisa, María Natalia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Lisa, María Natalia. Institut Pasteur de Montevideo. Laboratorio de Microbiología Molecular y Estructural; Uruguay.es
dc.description.filFil: Palacios, Antonela R. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Aitha, Mahesh. Miami University. Department of Chemistry and Biochemistry; United States.es
dc.description.filFil: González, Mariano Martín. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Moreno, Diego M. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR-CONICET); Argentina.es
dc.description.filFil: Moreno, Diego M. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Química General e Inorgánica; Argentina.es
dc.description.filFil: Crowder, Michael W. Miami University. Department of Chemistry and Biochemistry; United States.es
dc.description.filFil: Bonomo, Robert A. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; United States.es
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University (CWRU). School of Medicine. Departments of Medicine, Molecular Biology and Microbiology; United States.es
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University CWRU - Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology. Case VA CARES; United States.es
dc.description.filFil: Spencer, James. University of Bristol. Faculty of Life Sciences. School of Cellular and Molecular Medicine; United Kingdom.es
dc.description.filFil: Tierney, David L. Miami University. Department of Chemistry and Biochemistry; United States.es
dc.description.filFil: Llarrull, Leticia Irene. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.es
dc.description.filFil: Llarrull, Leticia Irene. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Biofísica; Argentina.es
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Vila, Alejandro J. Case Western Reserve University CWRU - Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology. Case VA CARES; United States.es
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Biofísica; Argentina.es
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica (ANPCyT): R01 AI100560-01es
dc.description.sponsorshipNational Institutes of Health (NIH): GM093987es
dc.description.sponsorshipNational Science Foundation (NSF): CHE-1151658es
dc.description.sponsorshipNational Institute of Biomedical Imaging and Bioengineering (NIBIB). Center for Synchrotron Biosciences: P30-EB-009998es
dc.formatapplication/pdf
dc.format.extent1-11es
dc.identifier.issn2041-1723es
dc.identifier.urihttp://hdl.handle.net/2133/20014
dc.language.isoenges
dc.publisherNaturees
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-017-00601-9es
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-017-00601-9es
dc.rightsopenAccesses
dc.rights.holderUniversidad Nacional de Rosarioes
dc.rights.holderLisa, María Nataliaes
dc.rights.holderPalacios, Antonela R.es
dc.rights.holderAitha, Maheshes
dc.rights.holderGonzález, Mariano Martínes
dc.rights.holderMoreno, Diego M.es
dc.rights.holderCrowder, Michael W.es
dc.rights.holderBonomo, Robert A.es
dc.rights.holderSpencer, Jameses
dc.rights.holderTierney, David L.es
dc.rights.holderLlarrull, Leticia Irenees
dc.rights.holderVila, Alejandro J.es
dc.rights.textAttribution 4.0 International (CC BY 4.0)es
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectMetallo-β-lactamaseses
dc.subjectCarbapenemses
dc.subjectReaction Mechanismes
dc.titleA general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamaseses
dc.titleA general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-beta-lactamaseses
dc.typearticle
dc.typeartículo
dc.typepublishedVersion
dc.type.collectionarticulo
dc.type.versionpublishedVersiones

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