The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii

Autores
Moran Barrio, Jorgelina; Giacone, Lucía; Brambilla, Luciano; Fabbri, Carolina; Viale, Alejandro Miguel
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Carbapenem resistance in the Gram-negative opportunistic pathogen Acinetobacter baumannii primarily stems from the overexpression of acquired class D serine β-lactamases, known as OXA carbapenemases. These enzymes exhibit weak carbapenemase activity and possess lipoprotein signal peptides. While the kinetic and structural aspects of OXA enzymes have been characterized, their biogenesis pathway has received little attention, despite potentially offering novel therapeutic targets. Here, we investigated the biosynthetic process of the OXA-58 carbapenemase in the model A. baumannii strain ATCC17978. [3H]palmitate labeling confirmed that the OXA-58 precursor is lipidated in vivo. Replacing the OXA-58 lipobox cysteine with alanine through site-directed mutagenesis demonstrated that, while the lipoprotein pathway is not essential for productive OXA-58 synthesis, it is crucial for achieving the high cellular OXA-58 levels A. baumannii needs to efficiently overcome carbapenem challenge. Lipidation significantly increased OXA-58 hydrophobicity, directing the carbapenemase to a membrane location, likely the outer membrane (OM), after periplasmic translocation. This specific localization is a critical step for accumulating the high periplasmic OXA-58 concentration necessary for carbapenem resistance. Furthermore, lipidation enabled the selective recruitment of OXA-58 into outer membrane vesicles (OMV), revealing a novel disposal mechanism for surplus OXA-58 production. In conclusion, the A. baumannii lipoprotein biosynthetic pathway facilitates both the high periplasmic OXA-58 concentration essential for a more efficient carbapenem resistance and the attendant selective removal of surplus OXA-58 production via OMV. These features were likely powerful drivers in the selection of the lipoprotein pathway for the overproduction of OXA carbapenemases among contemporary A. baumannii strains subjected to carbapenem challenge.
Fil: Moran Barrio, Jorgelina. 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: Giacone, Lucía. 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: Brambilla, Luciano. 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: Fabbri, Carolina. 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: Viale, Alejandro Miguel. 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
Acinetobacter baumannii
carbapenem resistance
OXA-58 lipoprotein
outer membrane vesicles
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:11336/281107
Acceder
id CONICETDig_fab8d3dbc9c00dd69ec34e6ac3867879
oai_identifier_str oai:ri.conicet.gov.ar:11336/281107
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumanniiMoran Barrio, JorgelinaGiacone, LucíaBrambilla, LucianoFabbri, CarolinaViale, Alejandro MiguelAcinetobacter baumanniicarbapenem resistanceOXA-58 lipoproteinouter membrane vesicleshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Carbapenem resistance in the Gram-negative opportunistic pathogen Acinetobacter baumannii primarily stems from the overexpression of acquired class D serine β-lactamases, known as OXA carbapenemases. These enzymes exhibit weak carbapenemase activity and possess lipoprotein signal peptides. While the kinetic and structural aspects of OXA enzymes have been characterized, their biogenesis pathway has received little attention, despite potentially offering novel therapeutic targets. Here, we investigated the biosynthetic process of the OXA-58 carbapenemase in the model A. baumannii strain ATCC17978. [3H]palmitate labeling confirmed that the OXA-58 precursor is lipidated in vivo. Replacing the OXA-58 lipobox cysteine with alanine through site-directed mutagenesis demonstrated that, while the lipoprotein pathway is not essential for productive OXA-58 synthesis, it is crucial for achieving the high cellular OXA-58 levels A. baumannii needs to efficiently overcome carbapenem challenge. Lipidation significantly increased OXA-58 hydrophobicity, directing the carbapenemase to a membrane location, likely the outer membrane (OM), after periplasmic translocation. This specific localization is a critical step for accumulating the high periplasmic OXA-58 concentration necessary for carbapenem resistance. Furthermore, lipidation enabled the selective recruitment of OXA-58 into outer membrane vesicles (OMV), revealing a novel disposal mechanism for surplus OXA-58 production. In conclusion, the A. baumannii lipoprotein biosynthetic pathway facilitates both the high periplasmic OXA-58 concentration essential for a more efficient carbapenem resistance and the attendant selective removal of surplus OXA-58 production via OMV. These features were likely powerful drivers in the selection of the lipoprotein pathway for the overproduction of OXA carbapenemases among contemporary A. baumannii strains subjected to carbapenem challenge.Fil: Moran Barrio, Jorgelina. 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: Giacone, Lucía. 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: Brambilla, Luciano. 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: Fabbri, Carolina. 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: Viale, Alejandro Miguel. 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 Microbiology2025-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/281107Moran Barrio, Jorgelina; Giacone, Lucía; Brambilla, Luciano; Fabbri, Carolina; Viale, Alejandro Miguel; The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 69; 12; 11-2025; 1-280066-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/aac.01099-25info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.01099-25info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-26T09:57:23Zoai:ri.conicet.gov.ar:11336/281107instacron: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:34982026-02-26 09:57:23.858CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
title The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
spellingShingle The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
Moran Barrio, Jorgelina
Acinetobacter baumannii
carbapenem resistance
OXA-58 lipoprotein
outer membrane vesicles
title_short The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
title_full The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
title_fullStr The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
title_full_unstemmed The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
title_sort The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii
dc.creator.none.fl_str_mv Moran Barrio, Jorgelina
Giacone, Lucía
Brambilla, Luciano
Fabbri, Carolina
Viale, Alejandro Miguel
author Moran Barrio, Jorgelina
author_facet Moran Barrio, Jorgelina
Giacone, Lucía
Brambilla, Luciano
Fabbri, Carolina
Viale, Alejandro Miguel
author_role author
author2 Giacone, Lucía
Brambilla, Luciano
Fabbri, Carolina
Viale, Alejandro Miguel
author2_role author
author
author
author
dc.subject.none.fl_str_mv Acinetobacter baumannii
carbapenem resistance
OXA-58 lipoprotein
outer membrane vesicles
topic Acinetobacter baumannii
carbapenem resistance
OXA-58 lipoprotein
outer membrane vesicles
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 resistance in the Gram-negative opportunistic pathogen Acinetobacter baumannii primarily stems from the overexpression of acquired class D serine β-lactamases, known as OXA carbapenemases. These enzymes exhibit weak carbapenemase activity and possess lipoprotein signal peptides. While the kinetic and structural aspects of OXA enzymes have been characterized, their biogenesis pathway has received little attention, despite potentially offering novel therapeutic targets. Here, we investigated the biosynthetic process of the OXA-58 carbapenemase in the model A. baumannii strain ATCC17978. [3H]palmitate labeling confirmed that the OXA-58 precursor is lipidated in vivo. Replacing the OXA-58 lipobox cysteine with alanine through site-directed mutagenesis demonstrated that, while the lipoprotein pathway is not essential for productive OXA-58 synthesis, it is crucial for achieving the high cellular OXA-58 levels A. baumannii needs to efficiently overcome carbapenem challenge. Lipidation significantly increased OXA-58 hydrophobicity, directing the carbapenemase to a membrane location, likely the outer membrane (OM), after periplasmic translocation. This specific localization is a critical step for accumulating the high periplasmic OXA-58 concentration necessary for carbapenem resistance. Furthermore, lipidation enabled the selective recruitment of OXA-58 into outer membrane vesicles (OMV), revealing a novel disposal mechanism for surplus OXA-58 production. In conclusion, the A. baumannii lipoprotein biosynthetic pathway facilitates both the high periplasmic OXA-58 concentration essential for a more efficient carbapenem resistance and the attendant selective removal of surplus OXA-58 production via OMV. These features were likely powerful drivers in the selection of the lipoprotein pathway for the overproduction of OXA carbapenemases among contemporary A. baumannii strains subjected to carbapenem challenge.
Fil: Moran Barrio, Jorgelina. 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: Giacone, Lucía. 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: Brambilla, Luciano. 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: Fabbri, Carolina. 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: Viale, Alejandro Miguel. 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 resistance in the Gram-negative opportunistic pathogen Acinetobacter baumannii primarily stems from the overexpression of acquired class D serine β-lactamases, known as OXA carbapenemases. These enzymes exhibit weak carbapenemase activity and possess lipoprotein signal peptides. While the kinetic and structural aspects of OXA enzymes have been characterized, their biogenesis pathway has received little attention, despite potentially offering novel therapeutic targets. Here, we investigated the biosynthetic process of the OXA-58 carbapenemase in the model A. baumannii strain ATCC17978. [3H]palmitate labeling confirmed that the OXA-58 precursor is lipidated in vivo. Replacing the OXA-58 lipobox cysteine with alanine through site-directed mutagenesis demonstrated that, while the lipoprotein pathway is not essential for productive OXA-58 synthesis, it is crucial for achieving the high cellular OXA-58 levels A. baumannii needs to efficiently overcome carbapenem challenge. Lipidation significantly increased OXA-58 hydrophobicity, directing the carbapenemase to a membrane location, likely the outer membrane (OM), after periplasmic translocation. This specific localization is a critical step for accumulating the high periplasmic OXA-58 concentration necessary for carbapenem resistance. Furthermore, lipidation enabled the selective recruitment of OXA-58 into outer membrane vesicles (OMV), revealing a novel disposal mechanism for surplus OXA-58 production. In conclusion, the A. baumannii lipoprotein biosynthetic pathway facilitates both the high periplasmic OXA-58 concentration essential for a more efficient carbapenem resistance and the attendant selective removal of surplus OXA-58 production via OMV. These features were likely powerful drivers in the selection of the lipoprotein pathway for the overproduction of OXA carbapenemases among contemporary A. baumannii strains subjected to carbapenem challenge.
publishDate 2025
dc.date.none.fl_str_mv 2025-11
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/11336/281107
Moran Barrio, Jorgelina; Giacone, Lucía; Brambilla, Luciano; Fabbri, Carolina; Viale, Alejandro Miguel; The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 69; 12; 11-2025; 1-28
0066-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/281107
identifier_str_mv Moran Barrio, Jorgelina; Giacone, Lucía; Brambilla, Luciano; Fabbri, Carolina; Viale, Alejandro Miguel; The lipoprotein biosynthesis pathway: key to OXA-mediated carbapenem resistance in Acinetobacter baumannii; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 69; 12; 11-2025; 1-28
0066-4804
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.01099-25
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 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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