Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility

Objectives: β-lactamases are the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria. Although there are β-lactamase inhibitors (BLIs) available, β-lactam-BLI combinations are increasingly being neutralised by diverse mechanisms of bacterial resistance. This study hypothe...

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Autores: Ferrer-Espada, R. (Raquel)|||/items/7d95fe44-bd06-4992-bbc6-c95d68c5dc20, Sánchez-Gómez, S. (Susana)|||/items/eab3b124-db58-45e2-af4a-7d7c24d1ab46, Pitts, B. (Betsey)|||/items/6da21bbf-601e-48a8-a78f-bddcee714dbb, Stewart, P.S. (Philip S.)|||/items/a201b30b-6adf-48b0-942a-60512369066c, Martinez-de-Tejada, G. (Guillermo)|||/items/d1daba26-b84c-4914-8630-f3a980ec3bc8
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/68570
Acceso en línea:https://hdl.handle.net/10171/68570
Access Level:acceso abierto
Palabra clave:Biofilm
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Synergy
β-lactamase inhibitor
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spelling Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibilityFerrer-Espada, R. (Raquel)|||/items/7d95fe44-bd06-4992-bbc6-c95d68c5dc20Sánchez-Gómez, S. (Susana)|||/items/eab3b124-db58-45e2-af4a-7d7c24d1ab46Pitts, B. (Betsey)|||/items/6da21bbf-601e-48a8-a78f-bddcee714dbbStewart, P.S. (Philip S.)|||/items/a201b30b-6adf-48b0-942a-60512369066cMartinez-de-Tejada, G. (Guillermo)|||/items/d1daba26-b84c-4914-8630-f3a980ec3bc8BiofilmEscherichia coliKlebsiella pneumoniaePseudomonas aeruginosaSynergyβ-lactamase inhibitorObjectives: β-lactamases are the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria. Although there are β-lactamase inhibitors (BLIs) available, β-lactam-BLI combinations are increasingly being neutralised by diverse mechanisms of bacterial resistance. This study hypothesised that permeability-increasing antimicrobial peptides (AMPs) could lower the amount of BLIs necessary to sensitise bacteria to antibiotics that are β-lactamase substrates. Methods: To test this hypothesis, checkerboard assays were performed to measure the ability of several AMPs to synergise with piperacillin, ticarcillin, amoxicillin, ampicillin, and ceftazidime in the presence of either tazobactam, clavulanic acid, sulbactam, aztreonam, phenylboronic acid (PBA), or oxacillin. Assays were performed using planktonic and biofilm-forming cells of Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae overexpressing β-lactamases. Results: Synergy between polymyxin B nonapeptide (PMBN) and tazobactam boosted piperacillin activity by a factor of 128 in Escherichia coli (from 256 to 2 mg/L, fractional inhibitory concentration index (FICI) ≤ 0.02) and by a factor of at least 64 in Klebsiella pneumoniae (from 1024 mg/L to 16 mg/L, FICI ≤ 0.05). Synergy between PMBN and PBA enhanced ceftazidime activity 133 times in Pseudomonas aeruginosa (from 16 mg/L to 0.12 mg/L, FICI ≤ 0.03). As a consequence, MICs of all the tested antibiotics were brought down to therapeutic range. In addition, the combinations also reduced several orders of magnitude the amount of inhibitor needed for antibiotic sensitisation. Ceftazidime/PBA/PMBN at 50 times the planktonic MIC caused a 10 million-fold reduction in the viability of mature biofilms. Conclusion: This study proved that AMPs can synergise with BLIs and that this phenomenon can be exploited to sensitise bacteria to antibiotics.ElsevierDadun. Depósito Académico Digital Universidad de Navarra20242024-01-2620202020-01-0120202020-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/68570reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/685702026-06-21T12:47:57Z
dc.title.none.fl_str_mv Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
title Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
spellingShingle Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
Ferrer-Espada, R. (Raquel)|||/items/7d95fe44-bd06-4992-bbc6-c95d68c5dc20
Biofilm
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Synergy
β-lactamase inhibitor
title_short Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
title_full Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
title_fullStr Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
title_full_unstemmed Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
title_sort Permeability enhancers sensitize β-lactamase-expressing Enterobacteriaceae and Pseudomonas aeruginosa to β-lactamase inhibitors, thereby restoring their β-lactam susceptibility
dc.creator.none.fl_str_mv Ferrer-Espada, R. (Raquel)|||/items/7d95fe44-bd06-4992-bbc6-c95d68c5dc20
Sánchez-Gómez, S. (Susana)|||/items/eab3b124-db58-45e2-af4a-7d7c24d1ab46
Pitts, B. (Betsey)|||/items/6da21bbf-601e-48a8-a78f-bddcee714dbb
Stewart, P.S. (Philip S.)|||/items/a201b30b-6adf-48b0-942a-60512369066c
Martinez-de-Tejada, G. (Guillermo)|||/items/d1daba26-b84c-4914-8630-f3a980ec3bc8
author Ferrer-Espada, R. (Raquel)|||/items/7d95fe44-bd06-4992-bbc6-c95d68c5dc20
author_facet Ferrer-Espada, R. (Raquel)|||/items/7d95fe44-bd06-4992-bbc6-c95d68c5dc20
Sánchez-Gómez, S. (Susana)|||/items/eab3b124-db58-45e2-af4a-7d7c24d1ab46
Pitts, B. (Betsey)|||/items/6da21bbf-601e-48a8-a78f-bddcee714dbb
Stewart, P.S. (Philip S.)|||/items/a201b30b-6adf-48b0-942a-60512369066c
Martinez-de-Tejada, G. (Guillermo)|||/items/d1daba26-b84c-4914-8630-f3a980ec3bc8
author_role author
author2 Sánchez-Gómez, S. (Susana)|||/items/eab3b124-db58-45e2-af4a-7d7c24d1ab46
Pitts, B. (Betsey)|||/items/6da21bbf-601e-48a8-a78f-bddcee714dbb
Stewart, P.S. (Philip S.)|||/items/a201b30b-6adf-48b0-942a-60512369066c
Martinez-de-Tejada, G. (Guillermo)|||/items/d1daba26-b84c-4914-8630-f3a980ec3bc8
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv Biofilm
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Synergy
β-lactamase inhibitor
topic Biofilm
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Synergy
β-lactamase inhibitor
description Objectives: β-lactamases are the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria. Although there are β-lactamase inhibitors (BLIs) available, β-lactam-BLI combinations are increasingly being neutralised by diverse mechanisms of bacterial resistance. This study hypothesised that permeability-increasing antimicrobial peptides (AMPs) could lower the amount of BLIs necessary to sensitise bacteria to antibiotics that are β-lactamase substrates. Methods: To test this hypothesis, checkerboard assays were performed to measure the ability of several AMPs to synergise with piperacillin, ticarcillin, amoxicillin, ampicillin, and ceftazidime in the presence of either tazobactam, clavulanic acid, sulbactam, aztreonam, phenylboronic acid (PBA), or oxacillin. Assays were performed using planktonic and biofilm-forming cells of Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae overexpressing β-lactamases. Results: Synergy between polymyxin B nonapeptide (PMBN) and tazobactam boosted piperacillin activity by a factor of 128 in Escherichia coli (from 256 to 2 mg/L, fractional inhibitory concentration index (FICI) ≤ 0.02) and by a factor of at least 64 in Klebsiella pneumoniae (from 1024 mg/L to 16 mg/L, FICI ≤ 0.05). Synergy between PMBN and PBA enhanced ceftazidime activity 133 times in Pseudomonas aeruginosa (from 16 mg/L to 0.12 mg/L, FICI ≤ 0.03). As a consequence, MICs of all the tested antibiotics were brought down to therapeutic range. In addition, the combinations also reduced several orders of magnitude the amount of inhibitor needed for antibiotic sensitisation. Ceftazidime/PBA/PMBN at 50 times the planktonic MIC caused a 10 million-fold reduction in the viability of mature biofilms. Conclusion: This study proved that AMPs can synergise with BLIs and that this phenomenon can be exploited to sensitise bacteria to antibiotics.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-01
2020
2020-01-01
2024
2024-01-26
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10171/68570
url https://hdl.handle.net/10171/68570
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
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
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra
instname:Universidad de Navarra
instname_str Universidad de Navarra
reponame_str Dadun. Depósito Académico Digital de la Universidad de Navarra
collection Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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