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dc.provenanceCONICET-
dc.creatorGonzalez, Mariano Martin-
dc.creatorKosmopoulou, Magda-
dc.creatorMojica, Maria F.-
dc.creatorCastillo, Valerie-
dc.creatorHinchliffe, Philip-
dc.creatorPettinati, Ilaria-
dc.creatorBrem, Jürgen-
dc.creatorSchofield, Christopher J.-
dc.creatorMahler, Graciela-
dc.creatorBonomo, Robert A.-
dc.creatorLlarrull, Leticia Irene-
dc.creatorSpencer, James-
dc.creatorVila, Alejandro Jose-
dc.date2018-07-24T17:29:40Z-
dc.date2018-07-24T17:29:40Z-
dc.date2016-01-
dc.date2018-07-20T18:02:38Z-
dc.date.accessioned2019-04-29T15:44:13Z-
dc.date.available2019-04-29T15:44:13Z-
dc.date.issued2018-07-24T17:29:40Z-
dc.date.issued2018-07-24T17:29:40Z-
dc.date.issued2016-01-
dc.date.issued2018-07-20T18:02:38Z-
dc.identifierGonzalez, Mariano Martin; Kosmopoulou, Magda; Mojica, Maria F.; Castillo, Valerie; Hinchliffe, Philip; et al.; Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase; American Chemical Society; ACS Infectious Diseases; 1; 11; 1-2016; 544-554-
dc.identifier2373-8227-
dc.identifierhttp://hdl.handle.net/11336/52964-
dc.identifierCONICET Digital-
dc.identifierCONICET-
dc.identifier.urihttp://rodna.bn.gov.ar:8080/jspui/handle/bnmm/300694-
dc.descriptionPathogenic Gram-negative bacteria resistant to almost all β-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-β-lactamases (MBLs) produced by these bacteria inactivate most β-lactam antibiotics, including the carbapenems, which are "last line therapies" for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of β-lactam substrates, which can be modified with metal-binding groups to target the MBL active site. Inspired by known interactions of MBLs with β-lactams, we designed four BTZs that behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (from 7 ± 1 to 19 ± 3 μM). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1-producing Escherichia coli. In vitro time kill cell-based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restore the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.-
dc.descriptionFil: Gonzalez, Mariano Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina-
dc.descriptionFil: Kosmopoulou, Magda. University Walk; Reino Unido-
dc.descriptionFil: Mojica, Maria F.. Case Western Reserve University; Estados Unidos-
dc.descriptionFil: Castillo, Valerie. Universidad de la República; Uruguay-
dc.descriptionFil: Hinchliffe, Philip. University Walk; Reino Unido-
dc.descriptionFil: Pettinati, Ilaria. University of Oxford; Reino Unido-
dc.descriptionFil: Brem, Jürgen. University of Oxford; Reino Unido-
dc.descriptionFil: Schofield, Christopher J.. University of Oxford; Reino Unido-
dc.descriptionFil: Mahler, Graciela. Universidad de la República; Uruguay-
dc.descriptionFil: Bonomo, Robert A.. Case Western Reserve University; Estados Unidos-
dc.descriptionFil: Llarrull, Leticia Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina-
dc.descriptionFil: Spencer, James. University Walk; Reino Unido-
dc.descriptionFil: Vila, Alejandro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina-
dc.formatapplication/pdf-
dc.formatapplication/pdf-
dc.formatapplication/pdf-
dc.languageeng-
dc.publisherAmerican Chemical Society-
dc.relationinfo:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1021/acsinfecdis.5b00046-
dc.relationinfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acsinfecdis.5b00046-
dc.rightsinfo:eu-repo/semantics/restrictedAccess-
dc.rightshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/-
dc.sourcereponame:CONICET Digital (CONICET)-
dc.sourceinstname:Consejo Nacional de Investigaciones Científicas y Técnicas-
dc.sourceinstacron:CONICET-
dc.source.urihttp://hdl.handle.net/11336/52964-
dc.subjectANTIBIOTIC RESISTANCE-
dc.subjectBISTHIAZOLIDINES-
dc.subjectINHIBITORS-
dc.subjectMETALLO-Β-LACTAMASE-
dc.subjectNDM-1-
dc.subjectOtras Ciencias Biológicas-
dc.subjectCiencias Biológicas-
dc.subjectCIENCIAS NATURALES Y EXACTAS-
dc.titleBisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase-
dc.typeinfo:eu-repo/semantics/article-
dc.typeinfo:eu-repo/semantics/publishedVersion-
dc.typeinfo:ar-repo/semantics/articulo-
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