Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium

Autores
Hogan, Andrew M.; Zisanur Rahman, A. S. M.; Motnenko, Anna; Natarajan, Aakash; Maydaniuk, Dustin T.; León, Laura Beltina; Batun, Zayra; Palacios, Armando; Bosch, Alejandra; Cardona, Silvia Teresa
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.
Fil: Hogan, Andrew M.. University of Manitoba; Canadá
Fil: Zisanur Rahman, A. S. M.. University of Manitoba; Canadá
Fil: Motnenko, Anna. University of Manitoba; Canadá
Fil: Natarajan, Aakash. University of Manitoba; Canadá
Fil: Maydaniuk, Dustin T.. University of Manitoba; Canadá
Fil: León, Laura Beltina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina
Fil: Batun, Zayra. University of Manitoba; Canadá
Fil: Palacios, Armando. University of Manitoba; Canadá
Fil: Bosch, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina
Fil: Cardona, Silvia Teresa. University of Manitoba; Canadá
Materia
MULTIDRUG RESISTANT BACTERIA
ANTIBIOTIC RESISTENCE
CELL ENVELOPE
BETA LACTAMS
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:11336/227195
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/227195
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacteriumHogan, Andrew M.Zisanur Rahman, A. S. M.Motnenko, AnnaNatarajan, AakashMaydaniuk, Dustin T.León, Laura BeltinaBatun, ZayraPalacios, ArmandoBosch, AlejandraCardona, Silvia TeresaMULTIDRUG RESISTANT BACTERIAANTIBIOTIC RESISTENCECELL ENVELOPEBETA LACTAMShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.Fil: Hogan, Andrew M.. University of Manitoba; CanadáFil: Zisanur Rahman, A. S. M.. University of Manitoba; CanadáFil: Motnenko, Anna. University of Manitoba; CanadáFil: Natarajan, Aakash. University of Manitoba; CanadáFil: Maydaniuk, Dustin T.. University of Manitoba; CanadáFil: León, Laura Beltina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Batun, Zayra. University of Manitoba; CanadáFil: Palacios, Armando. University of Manitoba; CanadáFil: Bosch, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Cardona, Silvia Teresa. University of Manitoba; CanadáSpringer2023-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/227195Hogan, Andrew M.; Zisanur Rahman, A. S. M.; Motnenko, Anna; Natarajan, Aakash; Maydaniuk, Dustin T.; et al.; Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium; Springer; Nature Communications; 14; 1; 8-2023; 1-212041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-023-40494-5info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-023-40494-5info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:34:13Zoai:ri.conicet.gov.ar:11336/227195instacron: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:34982025-11-12 09:34:14.147CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
title Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
spellingShingle Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
Hogan, Andrew M.
MULTIDRUG RESISTANT BACTERIA
ANTIBIOTIC RESISTENCE
CELL ENVELOPE
BETA LACTAMS
title_short Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
title_full Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
title_fullStr Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
title_full_unstemmed Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
title_sort Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium
dc.creator.none.fl_str_mv Hogan, Andrew M.
Zisanur Rahman, A. S. M.
Motnenko, Anna
Natarajan, Aakash
Maydaniuk, Dustin T.
León, Laura Beltina
Batun, Zayra
Palacios, Armando
Bosch, Alejandra
Cardona, Silvia Teresa
author Hogan, Andrew M.
author_facet Hogan, Andrew M.
Zisanur Rahman, A. S. M.
Motnenko, Anna
Natarajan, Aakash
Maydaniuk, Dustin T.
León, Laura Beltina
Batun, Zayra
Palacios, Armando
Bosch, Alejandra
Cardona, Silvia Teresa
author_role author
author2 Zisanur Rahman, A. S. M.
Motnenko, Anna
Natarajan, Aakash
Maydaniuk, Dustin T.
León, Laura Beltina
Batun, Zayra
Palacios, Armando
Bosch, Alejandra
Cardona, Silvia Teresa
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MULTIDRUG RESISTANT BACTERIA
ANTIBIOTIC RESISTENCE
CELL ENVELOPE
BETA LACTAMS
topic MULTIDRUG RESISTANT BACTERIA
ANTIBIOTIC RESISTENCE
CELL ENVELOPE
BETA LACTAMS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.
Fil: Hogan, Andrew M.. University of Manitoba; Canadá
Fil: Zisanur Rahman, A. S. M.. University of Manitoba; Canadá
Fil: Motnenko, Anna. University of Manitoba; Canadá
Fil: Natarajan, Aakash. University of Manitoba; Canadá
Fil: Maydaniuk, Dustin T.. University of Manitoba; Canadá
Fil: León, Laura Beltina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina
Fil: Batun, Zayra. University of Manitoba; Canadá
Fil: Palacios, Armando. University of Manitoba; Canadá
Fil: Bosch, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina
Fil: Cardona, Silvia Teresa. University of Manitoba; Canadá
description The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.
publishDate 2023
dc.date.none.fl_str_mv 2023-08
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/11336/227195
Hogan, Andrew M.; Zisanur Rahman, A. S. M.; Motnenko, Anna; Natarajan, Aakash; Maydaniuk, Dustin T.; et al.; Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium; Springer; Nature Communications; 14; 1; 8-2023; 1-21
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/227195
identifier_str_mv Hogan, Andrew M.; Zisanur Rahman, A. S. M.; Motnenko, Anna; Natarajan, Aakash; Maydaniuk, Dustin T.; et al.; Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium; Springer; Nature Communications; 14; 1; 8-2023; 1-21
2041-1723
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://www.nature.com/articles/s41467-023-40494-5
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-023-40494-5
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
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
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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