Quinolone Resistance Reversion by Targeting the SOS Response.
Suppression of the SOS response has been postulated as a therapeutic strategy for potentiating antimicrobial agents. We aimed to evaluate the impact of its suppression on reversing resistance using a model of isogenic strains of Escherichia coli representing multiple levels of quinolone resistance....
| Autores: | , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/25223 |
| Acceso en línea: | https://hdl.handle.net/20.500.12105/25223 |
| Access Level: | acceso abierto |
| Palabra clave: | RecA SOS response Quinolones Resensitization of antibiotic-resistant bacteria Resistance reversion Anti-Bacterial Agents Chromosomes, Bacterial Drug Resistance, Bacterial Escherichia coli Microbial Sensitivity Tests Mutation Phenotype Plasmids SOS Response, Genetics |
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Quinolone Resistance Reversion by Targeting the SOS Response.Recacha, EMachuca, JDíaz de Alba, PRamos-Güelfo, MDocobo-Pérez, FRodriguez-Beltrán, JBlázquez, JPascual, ARodrguez-Martínez, J MRecASOS responseQuinolonesResensitization of antibiotic-resistant bacteriaResistance reversionAnti-Bacterial AgentsChromosomes, BacterialDrug Resistance, BacterialEscherichia coliMicrobial Sensitivity TestsMutationPhenotypePlasmidsQuinolonesSOS Response, GeneticsSuppression of the SOS response has been postulated as a therapeutic strategy for potentiating antimicrobial agents. We aimed to evaluate the impact of its suppression on reversing resistance using a model of isogenic strains of Escherichia coli representing multiple levels of quinolone resistance. E. coli mutants exhibiting a spectrum of SOS activity were constructed from isogenic strains carrying quinolone resistance mechanisms with susceptible and resistant phenotypes. Changes in susceptibility were evaluated by static (MICs) and dynamic (killing curves or flow cytometry) methodologies. A peritoneal sepsis murine model was used to evaluate in vivo impact. Suppression of the SOS response was capable of resensitizing mutant strains with genes encoding three or four different resistance mechanisms (up to 15-fold reductions in MICs). Killing curve assays showed a clear disadvantage for survival (Δlog10 CFU per milliliter [CFU/ml] of 8 log units after 24 h), and the in vivo efficacy of ciprofloxacin was significantly enhanced (Δlog10 CFU/g of 1.76 log units) in resistant strains with a suppressed SOS response. This effect was evident even after short periods (60 min) of exposure. Suppression of the SOS response reverses antimicrobial resistance across a range of E. coli phenotypes from reduced susceptibility to highly resistant, playing a significant role in increasing the in vivo efficacy.IMPORTANCE The rapid rise of antibiotic resistance in bacterial pathogens is now considered a major global health crisis. New strategies are needed to block the development of resistance and to extend the life of antibiotics. The SOS response is a promising target for developing therapeutics to reduce the acquisition of antibiotic resistance and enhance the bactericidal activity of antimicrobial agents such as quinolones. Significant questions remain regarding its impact as a strategy for the reversion or resensitization of antibiotic-resistant bacteria. To address this question, we have generated E. coli mutants that exhibited a spectrum of SOS activity, ranging from a natural SOS response to a hypoinducible or constitutively suppressed response. We tested the effects of these mutations on quinolone resistance reversion under therapeutic concentrations in a set of isogenic strains carrying different combinations of chromosome- and plasmid-mediated quinolone resistance mechanisms with susceptible, low-level quinolone resistant, resistant, and highly resistant phenotypes. Our comprehensive analysis opens up a new strategy for reversing drug resistance by targeting the SOS response.20242024-10-2320172017-10-1020172017-10-10research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttps://hdl.handle.net/20.500.12105/25223reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/252232026-06-12T12:43:37Z |
| dc.title.none.fl_str_mv |
Quinolone Resistance Reversion by Targeting the SOS Response. |
| title |
Quinolone Resistance Reversion by Targeting the SOS Response. |
| spellingShingle |
Quinolone Resistance Reversion by Targeting the SOS Response. Recacha, E RecA SOS response Quinolones Resensitization of antibiotic-resistant bacteria Resistance reversion Anti-Bacterial Agents Chromosomes, Bacterial Drug Resistance, Bacterial Escherichia coli Microbial Sensitivity Tests Mutation Phenotype Plasmids Quinolones SOS Response, Genetics |
| title_short |
Quinolone Resistance Reversion by Targeting the SOS Response. |
| title_full |
Quinolone Resistance Reversion by Targeting the SOS Response. |
| title_fullStr |
Quinolone Resistance Reversion by Targeting the SOS Response. |
| title_full_unstemmed |
Quinolone Resistance Reversion by Targeting the SOS Response. |
| title_sort |
Quinolone Resistance Reversion by Targeting the SOS Response. |
| dc.creator.none.fl_str_mv |
Recacha, E Machuca, J Díaz de Alba, P Ramos-Güelfo, M Docobo-Pérez, F Rodriguez-Beltrán, J Blázquez, J Pascual, A Rodrguez-Martínez, J M |
| author |
Recacha, E |
| author_facet |
Recacha, E Machuca, J Díaz de Alba, P Ramos-Güelfo, M Docobo-Pérez, F Rodriguez-Beltrán, J Blázquez, J Pascual, A Rodrguez-Martínez, J M |
| author_role |
author |
| author2 |
Machuca, J Díaz de Alba, P Ramos-Güelfo, M Docobo-Pérez, F Rodriguez-Beltrán, J Blázquez, J Pascual, A Rodrguez-Martínez, J M |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
|
| dc.subject.none.fl_str_mv |
RecA SOS response Quinolones Resensitization of antibiotic-resistant bacteria Resistance reversion Anti-Bacterial Agents Chromosomes, Bacterial Drug Resistance, Bacterial Escherichia coli Microbial Sensitivity Tests Mutation Phenotype Plasmids Quinolones SOS Response, Genetics |
| topic |
RecA SOS response Quinolones Resensitization of antibiotic-resistant bacteria Resistance reversion Anti-Bacterial Agents Chromosomes, Bacterial Drug Resistance, Bacterial Escherichia coli Microbial Sensitivity Tests Mutation Phenotype Plasmids Quinolones SOS Response, Genetics |
| description |
Suppression of the SOS response has been postulated as a therapeutic strategy for potentiating antimicrobial agents. We aimed to evaluate the impact of its suppression on reversing resistance using a model of isogenic strains of Escherichia coli representing multiple levels of quinolone resistance. E. coli mutants exhibiting a spectrum of SOS activity were constructed from isogenic strains carrying quinolone resistance mechanisms with susceptible and resistant phenotypes. Changes in susceptibility were evaluated by static (MICs) and dynamic (killing curves or flow cytometry) methodologies. A peritoneal sepsis murine model was used to evaluate in vivo impact. Suppression of the SOS response was capable of resensitizing mutant strains with genes encoding three or four different resistance mechanisms (up to 15-fold reductions in MICs). Killing curve assays showed a clear disadvantage for survival (Δlog10 CFU per milliliter [CFU/ml] of 8 log units after 24 h), and the in vivo efficacy of ciprofloxacin was significantly enhanced (Δlog10 CFU/g of 1.76 log units) in resistant strains with a suppressed SOS response. This effect was evident even after short periods (60 min) of exposure. Suppression of the SOS response reverses antimicrobial resistance across a range of E. coli phenotypes from reduced susceptibility to highly resistant, playing a significant role in increasing the in vivo efficacy.IMPORTANCE The rapid rise of antibiotic resistance in bacterial pathogens is now considered a major global health crisis. New strategies are needed to block the development of resistance and to extend the life of antibiotics. The SOS response is a promising target for developing therapeutics to reduce the acquisition of antibiotic resistance and enhance the bactericidal activity of antimicrobial agents such as quinolones. Significant questions remain regarding its impact as a strategy for the reversion or resensitization of antibiotic-resistant bacteria. To address this question, we have generated E. coli mutants that exhibited a spectrum of SOS activity, ranging from a natural SOS response to a hypoinducible or constitutively suppressed response. We tested the effects of these mutations on quinolone resistance reversion under therapeutic concentrations in a set of isogenic strains carrying different combinations of chromosome- and plasmid-mediated quinolone resistance mechanisms with susceptible, low-level quinolone resistant, resistant, and highly resistant phenotypes. Our comprehensive analysis opens up a new strategy for reversing drug resistance by targeting the SOS response. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 2017-10-10 2017 2017-10-10 2024 2024-10-23 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/20.500.12105/25223 |
| url |
https://hdl.handle.net/20.500.12105/25223 |
| 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.source.none.fl_str_mv |
reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII) |
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Instituto de Salud Carlos III (ISCIII) |
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Repisalud |
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Repisalud |
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15.812429 |