Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa

Cefiderocol/xeruborbactam is a novel β-lactam/β-lactamase inhibitor combination in which the siderophore-cephalosporin cefiderocol is paired with xeruborbactam, a broad-spectrum inhibitor that targets class A to D β-lactamases. We evaluated the contribution of resistance mechanisms to cefiderocol/xe...

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Autores: González-Pinto, Lucía, Gomis Font, Maria Antònia, Pérez-Rodríguez, Gloria, Blanco-Martín, Tania, Rodríguez-Pallares, Salud, Sánchez-Peña, Lucía, Beceiro, Alejandro, Bou, Germán, Jeannot, Katy, Oliver, Antonio, Arca-Suárez, Jorge
Formato: artículo
Fecha de publicación:2025
País:España
Recursos:Conselleria de Salut i Consum del Govern de les Illes Balears
Repositorio:Docusalut
Idioma:inglés
OAI Identifier:oai:docusalut.com:20.500.13003/26193
Acesso em linha:https://hdl.handle.net/20.500.13003/26193
Access Level:acceso abierto
Palavra-chave:Pseudomonas aeruginosa
Cefiderocol
beta-Lactams
beta-Lactam Resistance
beta-Lactamase Inhibitors
beta-Lactamas
Resistencia betalactámica
Inhibidores de beta-Lactamasas
cefiderocol
mutational mechanisms
taniborbactam
xeruborbactam
β-lactam
β-lactam resistance
β-lactamase
β-lactamase inhibitor
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spelling Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosaGonzález-Pinto, LucíaGomis Font, Maria AntòniaPérez-Rodríguez, GloriaBlanco-Martín, TaniaRodríguez-Pallares, SaludSánchez-Peña, LucíaBeceiro, AlejandroBou, GermánJeannot, KatyOliver, AntonioArca-Suárez, JorgePseudomonas aeruginosaCefiderocolbeta-Lactamsbeta-Lactam Resistancebeta-Lactamase InhibitorsPseudomonas aeruginosaCefiderocolbeta-LactamasResistencia betalactámicaInhibidores de beta-LactamasasPseudomonas aeruginosacefiderocolmutational mechanismstaniborbactamxeruborbactamβ-lactamβ-lactam resistanceβ-lactamaseβ-lactamase inhibitorCefiderocol/xeruborbactam is a novel β-lactam/β-lactamase inhibitor combination in which the siderophore-cephalosporin cefiderocol is paired with xeruborbactam, a broad-spectrum inhibitor that targets class A to D β-lactamases. We evaluated the contribution of resistance mechanisms to cefiderocol/xeruborbactam susceptibility. A panel of 61 . PAO1 derivatives was tested, including 20 knockout mutants representing key chromosomal resistance mechanisms (e.g., overexpression, efflux upregulation, porin loss, iron uptake deficiency) and 41 transformants producing major circulating β-lactamases. Xeruborbactam was assessed in combination with cefiderocol and cefepime at 4 and 8 mg/L and compared with taniborbactam. Additionally, 99 cefiderocol-resistant clinical isolates were evaluated. Cefiderocol/xeruborbactam retained activity against most mutants with chromosomally encoded resistance mechanisms. However, the defective mutant yielded increased cefiderocol minimum inhibitory concentrations (MIC = 2 mg/L), which could not be restored by xeruborbactam. Xeruborbactam significantly increased the activity of cefiderocol against the majority of PAO1 transformants, including those producing PER-1, SHV-12, KPC Ω-loop mutants, or NDM variants. Cefiderocol/xeruborbactam was active against IMP-type MBLs (which only weakly hydrolyze cefiderocol), including xeruborbactam-resistant enzymes. Relative to taniborbactam, xeruborbactam-based combinations showed similar activity against PAO1 transformants, but with slightly higher MIC values when tested against metallo-β-lactamase producers. This MIC increase in xeruborbactam-based combinations was partly because of the constitutive MexAB-OprM efflux in the background, as confirmed with PAO1 efflux mutants. Importantly, xeruborbactam restored susceptibility in 78% of 99 cefiderocol-resistant strains, reducing the MIC from 64 to 4 mg/L. Cefiderocol/xeruborbactam shows promising activity against .20252025-10-2120252025-10-21research articlehttp://purl.org/coar/resource_type/c_2df8fbb1info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.13003/26193reponame:Docusalutinstname:Conselleria de Salut i Consum del Govern de les Illes BalearsInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docusalut.com:20.500.13003/261932026-06-22T12:44:07Z
dc.title.none.fl_str_mv Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
title Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
spellingShingle Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
González-Pinto, Lucía
Pseudomonas aeruginosa
Cefiderocol
beta-Lactams
beta-Lactam Resistance
beta-Lactamase Inhibitors
Pseudomonas aeruginosa
Cefiderocol
beta-Lactamas
Resistencia betalactámica
Inhibidores de beta-Lactamasas
Pseudomonas aeruginosa
cefiderocol
mutational mechanisms
taniborbactam
xeruborbactam
β-lactam
β-lactam resistance
β-lactamase
β-lactamase inhibitor
title_short Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
title_full Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
title_fullStr Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
title_full_unstemmed Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
title_sort Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
dc.creator.none.fl_str_mv González-Pinto, Lucía
Gomis Font, Maria Antònia
Pérez-Rodríguez, Gloria
Blanco-Martín, Tania
Rodríguez-Pallares, Salud
Sánchez-Peña, Lucía
Beceiro, Alejandro
Bou, Germán
Jeannot, Katy
Oliver, Antonio
Arca-Suárez, Jorge
author González-Pinto, Lucía
author_facet González-Pinto, Lucía
Gomis Font, Maria Antònia
Pérez-Rodríguez, Gloria
Blanco-Martín, Tania
Rodríguez-Pallares, Salud
Sánchez-Peña, Lucía
Beceiro, Alejandro
Bou, Germán
Jeannot, Katy
Oliver, Antonio
Arca-Suárez, Jorge
author_role author
author2 Gomis Font, Maria Antònia
Pérez-Rodríguez, Gloria
Blanco-Martín, Tania
Rodríguez-Pallares, Salud
Sánchez-Peña, Lucía
Beceiro, Alejandro
Bou, Germán
Jeannot, Katy
Oliver, Antonio
Arca-Suárez, Jorge
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Pseudomonas aeruginosa
Cefiderocol
beta-Lactams
beta-Lactam Resistance
beta-Lactamase Inhibitors
Pseudomonas aeruginosa
Cefiderocol
beta-Lactamas
Resistencia betalactámica
Inhibidores de beta-Lactamasas
Pseudomonas aeruginosa
cefiderocol
mutational mechanisms
taniborbactam
xeruborbactam
β-lactam
β-lactam resistance
β-lactamase
β-lactamase inhibitor
topic Pseudomonas aeruginosa
Cefiderocol
beta-Lactams
beta-Lactam Resistance
beta-Lactamase Inhibitors
Pseudomonas aeruginosa
Cefiderocol
beta-Lactamas
Resistencia betalactámica
Inhibidores de beta-Lactamasas
Pseudomonas aeruginosa
cefiderocol
mutational mechanisms
taniborbactam
xeruborbactam
β-lactam
β-lactam resistance
β-lactamase
β-lactamase inhibitor
description Cefiderocol/xeruborbactam is a novel β-lactam/β-lactamase inhibitor combination in which the siderophore-cephalosporin cefiderocol is paired with xeruborbactam, a broad-spectrum inhibitor that targets class A to D β-lactamases. We evaluated the contribution of resistance mechanisms to cefiderocol/xeruborbactam susceptibility. A panel of 61 . PAO1 derivatives was tested, including 20 knockout mutants representing key chromosomal resistance mechanisms (e.g., overexpression, efflux upregulation, porin loss, iron uptake deficiency) and 41 transformants producing major circulating β-lactamases. Xeruborbactam was assessed in combination with cefiderocol and cefepime at 4 and 8 mg/L and compared with taniborbactam. Additionally, 99 cefiderocol-resistant clinical isolates were evaluated. Cefiderocol/xeruborbactam retained activity against most mutants with chromosomally encoded resistance mechanisms. However, the defective mutant yielded increased cefiderocol minimum inhibitory concentrations (MIC = 2 mg/L), which could not be restored by xeruborbactam. Xeruborbactam significantly increased the activity of cefiderocol against the majority of PAO1 transformants, including those producing PER-1, SHV-12, KPC Ω-loop mutants, or NDM variants. Cefiderocol/xeruborbactam was active against IMP-type MBLs (which only weakly hydrolyze cefiderocol), including xeruborbactam-resistant enzymes. Relative to taniborbactam, xeruborbactam-based combinations showed similar activity against PAO1 transformants, but with slightly higher MIC values when tested against metallo-β-lactamase producers. This MIC increase in xeruborbactam-based combinations was partly because of the constitutive MexAB-OprM efflux in the background, as confirmed with PAO1 efflux mutants. Importantly, xeruborbactam restored susceptibility in 78% of 99 cefiderocol-resistant strains, reducing the MIC from 64 to 4 mg/L. Cefiderocol/xeruborbactam shows promising activity against .
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-10-21
2025
2025-10-21
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.13003/26193
url https://hdl.handle.net/20.500.13003/26193
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Docusalut
instname:Conselleria de Salut i Consum del Govern de les Illes Balears
instname_str Conselleria de Salut i Consum del Govern de les Illes Balears
reponame_str Docusalut
collection Docusalut
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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