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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/227195
Ver los metadatos del registro completo
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oai:ri.conicet.gov.ar:11336/227195 |
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CONICET Digital (CONICET) |
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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 Técnicas2025-10-15T14:23:57Zoai: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:34982025-10-15 14:23:57.397CONICET 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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1846082656214712320 |
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13.22299 |