Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics

Autores
Fishovitz, Jennifer; Rojas Altuve, Alzoray; Otero, Lisandro Horacio; Dawley, Matthew; Carrasco López, Cesar; Chang, Mayland; Hermoso, Juan Antonio; Mobashery, Shahriar
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillinresistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
Fil: Fishovitz, Jennifer. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
Fil: Rojas Altuve, Alzoray. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España
Fil: Otero, Lisandro Horacio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Dawley, Matthew. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
Fil: Carrasco López, Cesar. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España
Fil: Chang, Mayland. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
Fil: Hermoso, Juan Antonio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España
Fil: Mobashery, Shahriar. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
Materia
Staphylococcus Aureus (Mrsa)
Penicillin-Binding Protein 2a
Ceftaroline
Antibiotic Resistance
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:11336/8345
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to AntibioticsFishovitz, JenniferRojas Altuve, AlzorayOtero, Lisandro HoracioDawley, MatthewCarrasco López, CesarChang, MaylandHermoso, Juan AntonioMobashery, ShahriarStaphylococcus Aureus (Mrsa)Penicillin-Binding Protein 2aCeftarolineAntibiotic Resistancehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillinresistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.Fil: Fishovitz, Jennifer. University of Notre Dame. Department of Chemistry and Biochemistry; Estados UnidosFil: Rojas Altuve, Alzoray. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; EspañaFil: Otero, Lisandro Horacio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Dawley, Matthew. University of Notre Dame. Department of Chemistry and Biochemistry; Estados UnidosFil: Carrasco López, Cesar. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; EspañaFil: Chang, Mayland. University of Notre Dame. Department of Chemistry and Biochemistry; Estados UnidosFil: Hermoso, Juan Antonio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; EspañaFil: Mobashery, Shahriar. University of Notre Dame. Department of Chemistry and Biochemistry; Estados UnidosAmerican Chemical Society2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8345Fishovitz, Jennifer; Rojas Altuve, Alzoray; Otero, Lisandro Horacio; Dawley, Matthew; Carrasco López, Cesar; et al.; Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics; American Chemical Society; Journal Of The American Chemical Society; 136; 28; -1-2014; 9814-98170002-7863enginfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/full/10.1021/ja5030657info:eu-repo/semantics/altIdentifier/doi/10.1021/ja5030657info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:42Zoai:ri.conicet.gov.ar:11336/8345instacron: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:34982025-09-03 09:59:42.473CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
title Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
spellingShingle Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
Fishovitz, Jennifer
Staphylococcus Aureus (Mrsa)
Penicillin-Binding Protein 2a
Ceftaroline
Antibiotic Resistance
title_short Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
title_full Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
title_fullStr Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
title_full_unstemmed Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
title_sort Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
dc.creator.none.fl_str_mv Fishovitz, Jennifer
Rojas Altuve, Alzoray
Otero, Lisandro Horacio
Dawley, Matthew
Carrasco López, Cesar
Chang, Mayland
Hermoso, Juan Antonio
Mobashery, Shahriar
author Fishovitz, Jennifer
author_facet Fishovitz, Jennifer
Rojas Altuve, Alzoray
Otero, Lisandro Horacio
Dawley, Matthew
Carrasco López, Cesar
Chang, Mayland
Hermoso, Juan Antonio
Mobashery, Shahriar
author_role author
author2 Rojas Altuve, Alzoray
Otero, Lisandro Horacio
Dawley, Matthew
Carrasco López, Cesar
Chang, Mayland
Hermoso, Juan Antonio
Mobashery, Shahriar
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Staphylococcus Aureus (Mrsa)
Penicillin-Binding Protein 2a
Ceftaroline
Antibiotic Resistance
topic Staphylococcus Aureus (Mrsa)
Penicillin-Binding Protein 2a
Ceftaroline
Antibiotic Resistance
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillinresistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
Fil: Fishovitz, Jennifer. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
Fil: Rojas Altuve, Alzoray. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España
Fil: Otero, Lisandro Horacio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Dawley, Matthew. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
Fil: Carrasco López, Cesar. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España
Fil: Chang, Mayland. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
Fil: Hermoso, Juan Antonio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España
Fil: Mobashery, Shahriar. University of Notre Dame. Department of Chemistry and Biochemistry; Estados Unidos
description Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillinresistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
publishDate 2014
dc.date.none.fl_str_mv 2014
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/11336/8345
Fishovitz, Jennifer; Rojas Altuve, Alzoray; Otero, Lisandro Horacio; Dawley, Matthew; Carrasco López, Cesar; et al.; Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics; American Chemical Society; Journal Of The American Chemical Society; 136; 28; -1-2014; 9814-9817
0002-7863
url http://hdl.handle.net/11336/8345
identifier_str_mv Fishovitz, Jennifer; Rojas Altuve, Alzoray; Otero, Lisandro Horacio; Dawley, Matthew; Carrasco López, Cesar; et al.; Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics; American Chemical Society; Journal Of The American Chemical Society; 136; 28; -1-2014; 9814-9817
0002-7863
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/full/10.1021/ja5030657
info:eu-repo/semantics/altIdentifier/doi/10.1021/ja5030657
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 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
_version_ 1842269596118155264
score 13.13397

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