Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase

Autores
Gonzalez, Mariano Martin; Kosmopoulou, Magda; Mojica, Maria F.; Castillo, Valerie; Hinchliffe, Philip; Pettinati, Ilaria; Brem, Jürgen; Schofield, Christopher J.; Mahler, Graciela; Bonomo, Robert A.; Llarrull, Leticia Irene; Spencer, James; Vila, Alejandro Jose
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Pathogenic 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.
Fil: 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
Fil: Kosmopoulou, Magda. University Walk; Reino Unido
Fil: Mojica, Maria F.. Case Western Reserve University; Estados Unidos
Fil: Castillo, Valerie. Universidad de la República; Uruguay
Fil: Hinchliffe, Philip. University Walk; Reino Unido
Fil: Pettinati, Ilaria. University of Oxford; Reino Unido
Fil: Brem, Jürgen. University of Oxford; Reino Unido
Fil: Schofield, Christopher J.. University of Oxford; Reino Unido
Fil: Mahler, Graciela. Universidad de la República; Uruguay
Fil: Bonomo, Robert A.. Case Western Reserve University; Estados Unidos
Fil: 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
Fil: Spencer, James. University Walk; Reino Unido
Fil: 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
Materia
Antibiotic Resistance
Bisthiazolidines
Inhibitors
Metallo-Β-Lactamase
Ndm-1
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/52964
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/52964
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 CarbapenemaseGonzalez, Mariano MartinKosmopoulou, MagdaMojica, Maria F.Castillo, ValerieHinchliffe, PhilipPettinati, IlariaBrem, JürgenSchofield, Christopher J.Mahler, GracielaBonomo, Robert A.Llarrull, Leticia IreneSpencer, JamesVila, Alejandro JoseAntibiotic ResistanceBisthiazolidinesInhibitorsMetallo-Β-LactamaseNdm-1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Pathogenic 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.Fil: 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; ArgentinaFil: Kosmopoulou, Magda. University Walk; Reino UnidoFil: Mojica, Maria F.. Case Western Reserve University; Estados UnidosFil: Castillo, Valerie. Universidad de la República; UruguayFil: Hinchliffe, Philip. University Walk; Reino UnidoFil: Pettinati, Ilaria. University of Oxford; Reino UnidoFil: Brem, Jürgen. University of Oxford; Reino UnidoFil: Schofield, Christopher J.. University of Oxford; Reino UnidoFil: Mahler, Graciela. Universidad de la República; UruguayFil: Bonomo, Robert A.. Case Western Reserve University; Estados UnidosFil: 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; ArgentinaFil: Spencer, James. University Walk; Reino UnidoFil: 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; ArgentinaAmerican Chemical Society2016-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/52964Gonzalez, 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; 544-5542373-8227CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/acsinfecdis.5b00046info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acsinfecdis.5b00046info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:02:07Zoai:ri.conicet.gov.ar:11336/52964instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:02:07.848CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
title Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
spellingShingle Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
Gonzalez, Mariano Martin
Antibiotic Resistance
Bisthiazolidines
Inhibitors
Metallo-Β-Lactamase
Ndm-1
title_short Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
title_full Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
title_fullStr Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
title_full_unstemmed Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
title_sort Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase
dc.creator.none.fl_str_mv Gonzalez, Mariano Martin
Kosmopoulou, Magda
Mojica, Maria F.
Castillo, Valerie
Hinchliffe, Philip
Pettinati, Ilaria
Brem, Jürgen
Schofield, Christopher J.
Mahler, Graciela
Bonomo, Robert A.
Llarrull, Leticia Irene
Spencer, James
Vila, Alejandro Jose
author Gonzalez, Mariano Martin
author_facet Gonzalez, Mariano Martin
Kosmopoulou, Magda
Mojica, Maria F.
Castillo, Valerie
Hinchliffe, Philip
Pettinati, Ilaria
Brem, Jürgen
Schofield, Christopher J.
Mahler, Graciela
Bonomo, Robert A.
Llarrull, Leticia Irene
Spencer, James
Vila, Alejandro Jose
author_role author
author2 Kosmopoulou, Magda
Mojica, Maria F.
Castillo, Valerie
Hinchliffe, Philip
Pettinati, Ilaria
Brem, Jürgen
Schofield, Christopher J.
Mahler, Graciela
Bonomo, Robert A.
Llarrull, Leticia Irene
Spencer, James
Vila, Alejandro Jose
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Antibiotic Resistance
Bisthiazolidines
Inhibitors
Metallo-Β-Lactamase
Ndm-1
topic Antibiotic Resistance
Bisthiazolidines
Inhibitors
Metallo-Β-Lactamase
Ndm-1
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Pathogenic 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.
Fil: 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
Fil: Kosmopoulou, Magda. University Walk; Reino Unido
Fil: Mojica, Maria F.. Case Western Reserve University; Estados Unidos
Fil: Castillo, Valerie. Universidad de la República; Uruguay
Fil: Hinchliffe, Philip. University Walk; Reino Unido
Fil: Pettinati, Ilaria. University of Oxford; Reino Unido
Fil: Brem, Jürgen. University of Oxford; Reino Unido
Fil: Schofield, Christopher J.. University of Oxford; Reino Unido
Fil: Mahler, Graciela. Universidad de la República; Uruguay
Fil: Bonomo, Robert A.. Case Western Reserve University; Estados Unidos
Fil: 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
Fil: Spencer, James. University Walk; Reino Unido
Fil: 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
description Pathogenic 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.
publishDate 2016
dc.date.none.fl_str_mv 2016-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/52964
Gonzalez, 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
2373-8227
CONICET Digital
CONICET
url http://hdl.handle.net/11336/52964
identifier_str_mv Gonzalez, 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
2373-8227
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/acsinfecdis.5b00046
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acsinfecdis.5b00046
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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