Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation

Autores
Bahr, Guillermo; Vitor Horen, Luisina; Bethel, Christopher R.; Bonomo, Robert A.; Gonzalez, Lisandro Javier; Vila, Alejandro Jose
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Carbapenem-resistant Enterobacteriaceae (CRE) are rapidly spreading and taking a staggering toll on all health care systems, largely due to the dissemination of genes coding for potent carbapenemases. An important family of carbapenemases are the Zn(II)-dependent β-lactamases, known as metallo-β-lactamases (MBLs). Among them, the New Delhi metallo-β-lactamase (NDM) has experienced the fastest and widest geographical spread. While other clinically important MBLs are soluble periplasmic enzymes, NDMs are lipoproteins anchored to the outer membrane in Gram-negative bacteria. This unique cellular localization endows NDMs with enhanced stability upon the Zn(II) starvation elicited by the immune system response at the sites of infection. Since the first report of NDM-1, new allelic variants (16 in total) have been identified in clinical isolates differing by a limited number of substitutions. Here, we show that these variants have evolved by accumulating mutations that enhance their stability or the Zn(II) binding affinity in vivo, overriding the most common evolutionary pressure acting on catalytic efficiency. We identified the ubiquitous substitution M154L as responsible for improving the Zn(II) binding capabilities of the NDM variants. These results also reveal that Zn(II) deprivation imposes a strict constraint on the evolution of this MBL, overriding the most common pressures acting on catalytic performance, and shed light on possible inhibitory strategies.
Fil: Bahr, Guillermo. 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: Vitor Horen, Luisina. 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: Bethel, Christopher R.. Louis Stokes Cleveland VA Medical Center; Estados Unidos
Fil: Bonomo, Robert A.. Louis Stokes Cleveland VA Medical Center; Estados Unidos
Fil: Gonzalez, Lisandro Javier. 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: 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
CARBAPENEMASE
METALLO-Β- LACTAMASE
NDM
NUTRITIONAL IMMUNITY
ZN(II) LIMITATION
Nivel de accesibilidad
acceso embargado
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:11336/50572
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/50572
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) DeprivationBahr, GuillermoVitor Horen, LuisinaBethel, Christopher R.Bonomo, Robert A.Gonzalez, Lisandro JavierVila, Alejandro JoseANTIBIOTIC RESISTANCECARBAPENEMASEMETALLO-Β- LACTAMASENDMNUTRITIONAL IMMUNITYZN(II) LIMITATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Carbapenem-resistant Enterobacteriaceae (CRE) are rapidly spreading and taking a staggering toll on all health care systems, largely due to the dissemination of genes coding for potent carbapenemases. An important family of carbapenemases are the Zn(II)-dependent β-lactamases, known as metallo-β-lactamases (MBLs). Among them, the New Delhi metallo-β-lactamase (NDM) has experienced the fastest and widest geographical spread. While other clinically important MBLs are soluble periplasmic enzymes, NDMs are lipoproteins anchored to the outer membrane in Gram-negative bacteria. This unique cellular localization endows NDMs with enhanced stability upon the Zn(II) starvation elicited by the immune system response at the sites of infection. Since the first report of NDM-1, new allelic variants (16 in total) have been identified in clinical isolates differing by a limited number of substitutions. Here, we show that these variants have evolved by accumulating mutations that enhance their stability or the Zn(II) binding affinity in vivo, overriding the most common evolutionary pressure acting on catalytic efficiency. We identified the ubiquitous substitution M154L as responsible for improving the Zn(II) binding capabilities of the NDM variants. These results also reveal that Zn(II) deprivation imposes a strict constraint on the evolution of this MBL, overriding the most common pressures acting on catalytic performance, and shed light on possible inhibitory strategies.Fil: Bahr, Guillermo. 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: Vitor Horen, Luisina. 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: Bethel, Christopher R.. Louis Stokes Cleveland VA Medical Center; Estados UnidosFil: Bonomo, Robert A.. Louis Stokes Cleveland VA Medical Center; Estados UnidosFil: Gonzalez, Lisandro Javier. 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: 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 Society for Microbiology2018-01info:eu-repo/date/embargoEnd/2018-08-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/50572Bahr, Guillermo; Vitor Horen, Luisina; Bethel, Christopher R.; Bonomo, Robert A.; Gonzalez, Lisandro Javier; et al.; Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 62; 1; 1-2018; 1-320066-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.01849-17info:eu-repo/semantics/altIdentifier/url/http://aac.asm.org/content/62/1/e01849-17info:eu-repo/semantics/embargoedAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:02Zoai:ri.conicet.gov.ar:11336/50572instacron: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 09:44:02.331CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
title Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
spellingShingle Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
Bahr, Guillermo
ANTIBIOTIC RESISTANCE
CARBAPENEMASE
METALLO-Β- LACTAMASE
NDM
NUTRITIONAL IMMUNITY
ZN(II) LIMITATION
title_short Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
title_full Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
title_fullStr Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
title_full_unstemmed Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
title_sort Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation
dc.creator.none.fl_str_mv Bahr, Guillermo
Vitor Horen, Luisina
Bethel, Christopher R.
Bonomo, Robert A.
Gonzalez, Lisandro Javier
Vila, Alejandro Jose
author Bahr, Guillermo
author_facet Bahr, Guillermo
Vitor Horen, Luisina
Bethel, Christopher R.
Bonomo, Robert A.
Gonzalez, Lisandro Javier
Vila, Alejandro Jose
author_role author
author2 Vitor Horen, Luisina
Bethel, Christopher R.
Bonomo, Robert A.
Gonzalez, Lisandro Javier
Vila, Alejandro Jose
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv ANTIBIOTIC RESISTANCE
CARBAPENEMASE
METALLO-Β- LACTAMASE
NDM
NUTRITIONAL IMMUNITY
ZN(II) LIMITATION
topic ANTIBIOTIC RESISTANCE
CARBAPENEMASE
METALLO-Β- LACTAMASE
NDM
NUTRITIONAL IMMUNITY
ZN(II) LIMITATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Carbapenem-resistant Enterobacteriaceae (CRE) are rapidly spreading and taking a staggering toll on all health care systems, largely due to the dissemination of genes coding for potent carbapenemases. An important family of carbapenemases are the Zn(II)-dependent β-lactamases, known as metallo-β-lactamases (MBLs). Among them, the New Delhi metallo-β-lactamase (NDM) has experienced the fastest and widest geographical spread. While other clinically important MBLs are soluble periplasmic enzymes, NDMs are lipoproteins anchored to the outer membrane in Gram-negative bacteria. This unique cellular localization endows NDMs with enhanced stability upon the Zn(II) starvation elicited by the immune system response at the sites of infection. Since the first report of NDM-1, new allelic variants (16 in total) have been identified in clinical isolates differing by a limited number of substitutions. Here, we show that these variants have evolved by accumulating mutations that enhance their stability or the Zn(II) binding affinity in vivo, overriding the most common evolutionary pressure acting on catalytic efficiency. We identified the ubiquitous substitution M154L as responsible for improving the Zn(II) binding capabilities of the NDM variants. These results also reveal that Zn(II) deprivation imposes a strict constraint on the evolution of this MBL, overriding the most common pressures acting on catalytic performance, and shed light on possible inhibitory strategies.
Fil: Bahr, Guillermo. 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: Vitor Horen, Luisina. 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: Bethel, Christopher R.. Louis Stokes Cleveland VA Medical Center; Estados Unidos
Fil: Bonomo, Robert A.. Louis Stokes Cleveland VA Medical Center; Estados Unidos
Fil: Gonzalez, Lisandro Javier. 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: 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 Carbapenem-resistant Enterobacteriaceae (CRE) are rapidly spreading and taking a staggering toll on all health care systems, largely due to the dissemination of genes coding for potent carbapenemases. An important family of carbapenemases are the Zn(II)-dependent β-lactamases, known as metallo-β-lactamases (MBLs). Among them, the New Delhi metallo-β-lactamase (NDM) has experienced the fastest and widest geographical spread. While other clinically important MBLs are soluble periplasmic enzymes, NDMs are lipoproteins anchored to the outer membrane in Gram-negative bacteria. This unique cellular localization endows NDMs with enhanced stability upon the Zn(II) starvation elicited by the immune system response at the sites of infection. Since the first report of NDM-1, new allelic variants (16 in total) have been identified in clinical isolates differing by a limited number of substitutions. Here, we show that these variants have evolved by accumulating mutations that enhance their stability or the Zn(II) binding affinity in vivo, overriding the most common evolutionary pressure acting on catalytic efficiency. We identified the ubiquitous substitution M154L as responsible for improving the Zn(II) binding capabilities of the NDM variants. These results also reveal that Zn(II) deprivation imposes a strict constraint on the evolution of this MBL, overriding the most common pressures acting on catalytic performance, and shed light on possible inhibitory strategies.
publishDate 2018
dc.date.none.fl_str_mv 2018-01
info:eu-repo/date/embargoEnd/2018-08-01
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/11336/50572
Bahr, Guillermo; Vitor Horen, Luisina; Bethel, Christopher R.; Bonomo, Robert A.; Gonzalez, Lisandro Javier; et al.; Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 62; 1; 1-2018; 1-32
0066-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/50572
identifier_str_mv Bahr, Guillermo; Vitor Horen, Luisina; Bethel, Christopher R.; Bonomo, Robert A.; Gonzalez, Lisandro Javier; et al.; Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) optimizes resistance under Zn(II) Deprivation; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 62; 1; 1-2018; 1-32
0066-4804
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.01849-17
info:eu-repo/semantics/altIdentifier/url/http://aac.asm.org/content/62/1/e01849-17
dc.rights.none.fl_str_mv info:eu-repo/semantics/embargoedAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv embargoedAccess
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
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
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 13.13397

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