The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam

Autores
Le Terrier, Christophe; Drusin, Salvador Iván; Nordmann, Patrice; Pitout, Johann; Peirano, Gisele; Vila, Alejandro Jose; Moreno, Diego Martin; Poirel, Laurent
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Metallo-β-lactamases (MBLs) of IMP type are not inhibited by currently commercialized β-lactamase inhibitors, including taniborbactam (TAN), which inhibits only NDM- and VIM-type enzymes. However, the development of xeruborbactam (XER), which additionally inhibits IMP enzymes, may provide effective drug combinations such as meropenem-XER (MEM-XER) against most MBL producers. Thirty-two IMP-producing clinical gram-negative isolates were tested for MEM-XER. Susceptibility testing of β-lactams with TAN or XER at 4 or 8 µg/mL was performed. Noticeably, MEM-XER remained ineffective against all IMP-producing Pseudomonas aeruginosa isolates. By contrast, supplementation with XER significantly lowered MEM MICs for several IMPproducing Enterobacterales isolates, except for isolates and recombinant E. coli strains producing IMP-6, IMP-10, IMP-14, and IMP-26. Interestingly, IMP-59 producers showed susceptibility to both TAN- and XER-based combinations, although IMP enzymes are not supposed to be inhibited by TAN. Determinations of 50% inhibitory concentration (IC50) values of XER showed values being >15-fold higher for IMP-6, IMP-10, IMP-14, and IMP-26 compared with IMP-1. Interestingly, the IC50 value of TAN for IMP-59 was found in the same range as that for NDM-1 (7 µM). Finally, structural analyses and molecular modeling simulations indicated that the Ser262Gly mutation in IMP-6 may alter the electronic properties of the active site, whereas the Phe residue in IMP-10 may exert a steric effect counteracting XER binding. Resistance to XER in IMP-6, IMP-10, IMP-14, and IMP-26 variants, conferring resistance to MEM-XER, might be considered a serious concern since MEM-XER will be supposed to be a salvage therapy for MBL-, and especially IMP-producing Enterobacterales infections.
Fil: Le Terrier, Christophe. University Hospitals Of Geneva (hug); Suiza. Universite de Fribourg;
Fil: Drusin, Salvador Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
Fil: Nordmann, Patrice. Universite de Fribourg; . Swiss National Reference Center for Emerging Antibiotic Resistance; Suiza
Fil: Pitout, Johann. University of Calgary; Canadá. University of Pretoria; Sudáfrica. Alberta Precision Laboratories; Canadá
Fil: Peirano, Gisele. University of Calgary; Canadá. Alberta Precision Laboratories; Canadá
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. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; Estados Unidos
Fil: Moreno, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
Fil: Poirel, Laurent. Universite de Fribourg; . Swiss National Reference Center for Emerging Antibiotic Resistance; Suiza
Materia
Metallo-beta-lactamase
IMP
Xeruborbactam
Carbapenemase
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/280837
Acceder
id CONICETDig_c4e9df9399ab3990b38ab37091633fec
oai_identifier_str oai:ri.conicet.gov.ar:11336/280837
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactamLe Terrier, ChristopheDrusin, Salvador IvánNordmann, PatricePitout, JohannPeirano, GiseleVila, Alejandro JoseMoreno, Diego MartinPoirel, LaurentMetallo-beta-lactamaseIMPXeruborbactamCarbapenemasehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Metallo-β-lactamases (MBLs) of IMP type are not inhibited by currently commercialized β-lactamase inhibitors, including taniborbactam (TAN), which inhibits only NDM- and VIM-type enzymes. However, the development of xeruborbactam (XER), which additionally inhibits IMP enzymes, may provide effective drug combinations such as meropenem-XER (MEM-XER) against most MBL producers. Thirty-two IMP-producing clinical gram-negative isolates were tested for MEM-XER. Susceptibility testing of β-lactams with TAN or XER at 4 or 8 µg/mL was performed. Noticeably, MEM-XER remained ineffective against all IMP-producing Pseudomonas aeruginosa isolates. By contrast, supplementation with XER significantly lowered MEM MICs for several IMPproducing Enterobacterales isolates, except for isolates and recombinant E. coli strains producing IMP-6, IMP-10, IMP-14, and IMP-26. Interestingly, IMP-59 producers showed susceptibility to both TAN- and XER-based combinations, although IMP enzymes are not supposed to be inhibited by TAN. Determinations of 50% inhibitory concentration (IC50) values of XER showed values being >15-fold higher for IMP-6, IMP-10, IMP-14, and IMP-26 compared with IMP-1. Interestingly, the IC50 value of TAN for IMP-59 was found in the same range as that for NDM-1 (7 µM). Finally, structural analyses and molecular modeling simulations indicated that the Ser262Gly mutation in IMP-6 may alter the electronic properties of the active site, whereas the Phe residue in IMP-10 may exert a steric effect counteracting XER binding. Resistance to XER in IMP-6, IMP-10, IMP-14, and IMP-26 variants, conferring resistance to MEM-XER, might be considered a serious concern since MEM-XER will be supposed to be a salvage therapy for MBL-, and especially IMP-producing Enterobacterales infections.Fil: Le Terrier, Christophe. University Hospitals Of Geneva (hug); Suiza. Universite de Fribourg;Fil: Drusin, Salvador Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Nordmann, Patrice. Universite de Fribourg; . Swiss National Reference Center for Emerging Antibiotic Resistance; SuizaFil: Pitout, Johann. University of Calgary; Canadá. University of Pretoria; Sudáfrica. Alberta Precision Laboratories; CanadáFil: Peirano, Gisele. University of Calgary; Canadá. Alberta Precision Laboratories; CanadáFil: 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. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; Estados UnidosFil: Moreno, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Poirel, Laurent. Universite de Fribourg; . Swiss National Reference Center for Emerging Antibiotic Resistance; SuizaAmerican Society for Microbiology2025-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/280837Le Terrier, Christophe; Drusin, Salvador Iván; Nordmann, Patrice; Pitout, Johann; Peirano, Gisele; et al.; The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 69; 7; 6-2025; 1-160066-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/aac.00297-25info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.00297-25info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-06T12:09:35Zoai:ri.conicet.gov.ar:11336/280837instacron: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:34982026-02-06 12:09:36.049CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
title The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
spellingShingle The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
Le Terrier, Christophe
Metallo-beta-lactamase
IMP
Xeruborbactam
Carbapenemase
title_short The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
title_full The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
title_fullStr The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
title_full_unstemmed The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
title_sort The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam
dc.creator.none.fl_str_mv Le Terrier, Christophe
Drusin, Salvador Iván
Nordmann, Patrice
Pitout, Johann
Peirano, Gisele
Vila, Alejandro Jose
Moreno, Diego Martin
Poirel, Laurent
author Le Terrier, Christophe
author_facet Le Terrier, Christophe
Drusin, Salvador Iván
Nordmann, Patrice
Pitout, Johann
Peirano, Gisele
Vila, Alejandro Jose
Moreno, Diego Martin
Poirel, Laurent
author_role author
author2 Drusin, Salvador Iván
Nordmann, Patrice
Pitout, Johann
Peirano, Gisele
Vila, Alejandro Jose
Moreno, Diego Martin
Poirel, Laurent
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Metallo-beta-lactamase
IMP
Xeruborbactam
Carbapenemase
topic Metallo-beta-lactamase
IMP
Xeruborbactam
Carbapenemase
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) of IMP type are not inhibited by currently commercialized β-lactamase inhibitors, including taniborbactam (TAN), which inhibits only NDM- and VIM-type enzymes. However, the development of xeruborbactam (XER), which additionally inhibits IMP enzymes, may provide effective drug combinations such as meropenem-XER (MEM-XER) against most MBL producers. Thirty-two IMP-producing clinical gram-negative isolates were tested for MEM-XER. Susceptibility testing of β-lactams with TAN or XER at 4 or 8 µg/mL was performed. Noticeably, MEM-XER remained ineffective against all IMP-producing Pseudomonas aeruginosa isolates. By contrast, supplementation with XER significantly lowered MEM MICs for several IMPproducing Enterobacterales isolates, except for isolates and recombinant E. coli strains producing IMP-6, IMP-10, IMP-14, and IMP-26. Interestingly, IMP-59 producers showed susceptibility to both TAN- and XER-based combinations, although IMP enzymes are not supposed to be inhibited by TAN. Determinations of 50% inhibitory concentration (IC50) values of XER showed values being >15-fold higher for IMP-6, IMP-10, IMP-14, and IMP-26 compared with IMP-1. Interestingly, the IC50 value of TAN for IMP-59 was found in the same range as that for NDM-1 (7 µM). Finally, structural analyses and molecular modeling simulations indicated that the Ser262Gly mutation in IMP-6 may alter the electronic properties of the active site, whereas the Phe residue in IMP-10 may exert a steric effect counteracting XER binding. Resistance to XER in IMP-6, IMP-10, IMP-14, and IMP-26 variants, conferring resistance to MEM-XER, might be considered a serious concern since MEM-XER will be supposed to be a salvage therapy for MBL-, and especially IMP-producing Enterobacterales infections.
Fil: Le Terrier, Christophe. University Hospitals Of Geneva (hug); Suiza. Universite de Fribourg;
Fil: Drusin, Salvador Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
Fil: Nordmann, Patrice. Universite de Fribourg; . Swiss National Reference Center for Emerging Antibiotic Resistance; Suiza
Fil: Pitout, Johann. University of Calgary; Canadá. University of Pretoria; Sudáfrica. Alberta Precision Laboratories; Canadá
Fil: Peirano, Gisele. University of Calgary; Canadá. Alberta Precision Laboratories; Canadá
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. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; Estados Unidos
Fil: Moreno, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
Fil: Poirel, Laurent. Universite de Fribourg; . Swiss National Reference Center for Emerging Antibiotic Resistance; Suiza
description Metallo-β-lactamases (MBLs) of IMP type are not inhibited by currently commercialized β-lactamase inhibitors, including taniborbactam (TAN), which inhibits only NDM- and VIM-type enzymes. However, the development of xeruborbactam (XER), which additionally inhibits IMP enzymes, may provide effective drug combinations such as meropenem-XER (MEM-XER) against most MBL producers. Thirty-two IMP-producing clinical gram-negative isolates were tested for MEM-XER. Susceptibility testing of β-lactams with TAN or XER at 4 or 8 µg/mL was performed. Noticeably, MEM-XER remained ineffective against all IMP-producing Pseudomonas aeruginosa isolates. By contrast, supplementation with XER significantly lowered MEM MICs for several IMPproducing Enterobacterales isolates, except for isolates and recombinant E. coli strains producing IMP-6, IMP-10, IMP-14, and IMP-26. Interestingly, IMP-59 producers showed susceptibility to both TAN- and XER-based combinations, although IMP enzymes are not supposed to be inhibited by TAN. Determinations of 50% inhibitory concentration (IC50) values of XER showed values being >15-fold higher for IMP-6, IMP-10, IMP-14, and IMP-26 compared with IMP-1. Interestingly, the IC50 value of TAN for IMP-59 was found in the same range as that for NDM-1 (7 µM). Finally, structural analyses and molecular modeling simulations indicated that the Ser262Gly mutation in IMP-6 may alter the electronic properties of the active site, whereas the Phe residue in IMP-10 may exert a steric effect counteracting XER binding. Resistance to XER in IMP-6, IMP-10, IMP-14, and IMP-26 variants, conferring resistance to MEM-XER, might be considered a serious concern since MEM-XER will be supposed to be a salvage therapy for MBL-, and especially IMP-producing Enterobacterales infections.
publishDate 2025
dc.date.none.fl_str_mv 2025-06
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/11336/280837
Le Terrier, Christophe; Drusin, Salvador Iván; Nordmann, Patrice; Pitout, Johann; Peirano, Gisele; et al.; The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 69; 7; 6-2025; 1-16
0066-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/280837
identifier_str_mv Le Terrier, Christophe; Drusin, Salvador Iván; Nordmann, Patrice; Pitout, Johann; Peirano, Gisele; et al.; The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 69; 7; 6-2025; 1-16
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/url/https://journals.asm.org/doi/10.1128/aac.00297-25
info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.00297-25
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
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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