Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes

Autores
Hinchliffe, Philip; Gonzalez, Javier Marcelo; Mojica, María; Gonzalez, Javier Marcelo; Castillo, Valerie; Saiz Garcia, Cecilia; Kosmopoulou, Magda; Tooke, Catherine; Llarrull, Leticia Irene; Mahler, Graciela; Bonomo, Robert; Vila, Alejandro Jose; Spencer, James
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both L- and D-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Ki sof6-15 μM or 36-84 μM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 μM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the L-BTZ enantiomers exhibit 100-fold lower Ki s (0.26-0.36 μM) than D-BTZs (26-29 μM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the L-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. D-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding.
Fil: Hinchliffe, Philip. University of Bristol; Reino Unido
Fil: Gonzalez, Javier Marcelo. 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: Mojica, María. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos
Fil: Gonzalez, Javier Marcelo. Universidad Nacional de Santiago del Estero. Instituto de Bionanotecnología del Noa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Bionanotecnología del Noa; Argentina
Fil: Castillo, Valerie. Universidad de la República; Uruguay
Fil: Saiz Garcia, Cecilia. Universidad de la República; Uruguay
Fil: Kosmopoulou, Magda. University of Bristol; Reino Unido
Fil: Tooke, Catherine. University of Bristol; Reino Unido
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: Mahler, Graciela. Universidad de la República; Uruguay
Fil: Bonomo, Robert. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos
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
Fil: Spencer, James. University of Bristol; Reino Unido
Materia
ANTIBIOTIC RESISTANCE
BISTHIAZOLIDINES
CARBAPENEMASE
INHIBITORS
METALLO-Β-LACTAMASE
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:11336/47337
Acceder
id CONICETDig_94f3dab1e890db7220765db23554ea76
oai_identifier_str oai:ri.conicet.gov.ar:11336/47337
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modesHinchliffe, PhilipGonzalez, Javier MarceloMojica, MaríaGonzalez, Javier MarceloCastillo, ValerieSaiz Garcia, CeciliaKosmopoulou, MagdaTooke, CatherineLlarrull, Leticia IreneMahler, GracielaBonomo, RobertVila, Alejandro JoseSpencer, JamesANTIBIOTIC RESISTANCEBISTHIAZOLIDINESCARBAPENEMASEINHIBITORSMETALLO-Β-LACTAMASEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both L- and D-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Ki sof6-15 μM or 36-84 μM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 μM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the L-BTZ enantiomers exhibit 100-fold lower Ki s (0.26-0.36 μM) than D-BTZs (26-29 μM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the L-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. D-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding.Fil: Hinchliffe, Philip. University of Bristol; Reino UnidoFil: Gonzalez, Javier Marcelo. 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: Mojica, María. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados UnidosFil: Gonzalez, Javier Marcelo. Universidad Nacional de Santiago del Estero. Instituto de Bionanotecnología del Noa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Bionanotecnología del Noa; ArgentinaFil: Castillo, Valerie. Universidad de la República; UruguayFil: Saiz Garcia, Cecilia. Universidad de la República; UruguayFil: Kosmopoulou, Magda. University of Bristol; Reino UnidoFil: Tooke, Catherine. University of Bristol; Reino UnidoFil: 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: Mahler, Graciela. Universidad de la República; UruguayFil: Bonomo, Robert. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados UnidosFil: 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; ArgentinaFil: Spencer, James. University of Bristol; Reino UnidoNational Academy of Sciences2016-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/47337Hinchliffe, Philip; Gonzalez, Javier Marcelo; Mojica, María; Gonzalez, Javier Marcelo; Castillo, Valerie; et al.; Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 113; 26; 6-2016; 3745-37540027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1601368113info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/113/26/E3745info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:16:35Zoai:ri.conicet.gov.ar:11336/47337instacron: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 13:16:35.346CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
title Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
spellingShingle Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
Hinchliffe, Philip
ANTIBIOTIC RESISTANCE
BISTHIAZOLIDINES
CARBAPENEMASE
INHIBITORS
METALLO-Β-LACTAMASE
title_short Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
title_full Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
title_fullStr Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
title_full_unstemmed Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
title_sort Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
dc.creator.none.fl_str_mv Hinchliffe, Philip
Gonzalez, Javier Marcelo
Mojica, María
Gonzalez, Javier Marcelo
Castillo, Valerie
Saiz Garcia, Cecilia
Kosmopoulou, Magda
Tooke, Catherine
Llarrull, Leticia Irene
Mahler, Graciela
Bonomo, Robert
Vila, Alejandro Jose
Spencer, James
author Hinchliffe, Philip
author_facet Hinchliffe, Philip
Gonzalez, Javier Marcelo
Mojica, María
Castillo, Valerie
Saiz Garcia, Cecilia
Kosmopoulou, Magda
Tooke, Catherine
Llarrull, Leticia Irene
Mahler, Graciela
Bonomo, Robert
Vila, Alejandro Jose
Spencer, James
author_role author
author2 Gonzalez, Javier Marcelo
Mojica, María
Castillo, Valerie
Saiz Garcia, Cecilia
Kosmopoulou, Magda
Tooke, Catherine
Llarrull, Leticia Irene
Mahler, Graciela
Bonomo, Robert
Vila, Alejandro Jose
Spencer, James
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ANTIBIOTIC RESISTANCE
BISTHIAZOLIDINES
CARBAPENEMASE
INHIBITORS
METALLO-Β-LACTAMASE
topic ANTIBIOTIC RESISTANCE
BISTHIAZOLIDINES
CARBAPENEMASE
INHIBITORS
METALLO-Β-LACTAMASE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both L- and D-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Ki sof6-15 μM or 36-84 μM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 μM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the L-BTZ enantiomers exhibit 100-fold lower Ki s (0.26-0.36 μM) than D-BTZs (26-29 μM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the L-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. D-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding.
Fil: Hinchliffe, Philip. University of Bristol; Reino Unido
Fil: Gonzalez, Javier Marcelo. 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: Mojica, María. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos
Fil: Gonzalez, Javier Marcelo. Universidad Nacional de Santiago del Estero. Instituto de Bionanotecnología del Noa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Bionanotecnología del Noa; Argentina
Fil: Castillo, Valerie. Universidad de la República; Uruguay
Fil: Saiz Garcia, Cecilia. Universidad de la República; Uruguay
Fil: Kosmopoulou, Magda. University of Bristol; Reino Unido
Fil: Tooke, Catherine. University of Bristol; Reino Unido
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: Mahler, Graciela. Universidad de la República; Uruguay
Fil: Bonomo, Robert. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos
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
Fil: Spencer, James. University of Bristol; Reino Unido
description Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both L- and D-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Ki sof6-15 μM or 36-84 μM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 μM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the L-BTZ enantiomers exhibit 100-fold lower Ki s (0.26-0.36 μM) than D-BTZs (26-29 μM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the L-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. D-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding.
publishDate 2016
dc.date.none.fl_str_mv 2016-06
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/11336/47337
Hinchliffe, Philip; Gonzalez, Javier Marcelo; Mojica, María; Gonzalez, Javier Marcelo; Castillo, Valerie; et al.; Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 113; 26; 6-2016; 3745-3754
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/47337
identifier_str_mv Hinchliffe, Philip; Gonzalez, Javier Marcelo; Mojica, María; Gonzalez, Javier Marcelo; Castillo, Valerie; et al.; Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 113; 26; 6-2016; 3745-3754
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1601368113
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/113/26/E3745
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
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
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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