Quinolone Resistance Reversion by Targeting the SOS Response

ABSTRACT 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 res...

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Autores principales:	E. Recacha, J. Machuca, P. Díaz de Alba, M. Ramos-Güelfo, F. Docobo-Pérez, J. Rodriguez-Beltrán, J. Blázquez, A. Pascual, J. M. Rodríguez-Martínez
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	RecA SOS response quinolones resensitization of antibiotic-resistant bacteria resistance reversion Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5f3554f2bb204dd1bdd6df4557674b5d
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spelling	oai:doaj.org-article:5f3554f2bb204dd1bdd6df4557674b5d2021-11-15T15:51:51ZQuinolone Resistance Reversion by Targeting the SOS Response10.1128/mBio.00971-172150-7511https://doaj.org/article/5f3554f2bb204dd1bdd6df4557674b5d2017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00971-17https://doaj.org/toc/2150-7511ABSTRACT 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.E. RecachaJ. MachucaP. Díaz de AlbaM. Ramos-GüelfoF. Docobo-PérezJ. Rodriguez-BeltránJ. BlázquezA. PascualJ. M. Rodríguez-MartínezAmerican Society for MicrobiologyarticleRecASOS responsequinolonesresensitization of antibiotic-resistant bacteriaresistance reversionMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	RecA SOS response quinolones resensitization of antibiotic-resistant bacteria resistance reversion Microbiology QR1-502
spellingShingle	RecA SOS response quinolones resensitization of antibiotic-resistant bacteria resistance reversion Microbiology QR1-502 E. Recacha J. Machuca P. Díaz de Alba M. Ramos-Güelfo F. Docobo-Pérez J. Rodriguez-Beltrán J. Blázquez A. Pascual J. M. Rodríguez-Martínez Quinolone Resistance Reversion by Targeting the SOS Response
description	ABSTRACT 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.
format	article
author	E. Recacha J. Machuca P. Díaz de Alba M. Ramos-Güelfo F. Docobo-Pérez J. Rodriguez-Beltrán J. Blázquez A. Pascual J. M. Rodríguez-Martínez
author_facet	E. Recacha J. Machuca P. Díaz de Alba M. Ramos-Güelfo F. Docobo-Pérez J. Rodriguez-Beltrán J. Blázquez A. Pascual J. M. Rodríguez-Martínez
author_sort	E. Recacha
title	Quinolone Resistance Reversion by Targeting the SOS Response
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
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/5f3554f2bb204dd1bdd6df4557674b5d
work_keys_str_mv	AT erecacha quinoloneresistancereversionbytargetingthesosresponse AT jmachuca quinoloneresistancereversionbytargetingthesosresponse AT pdiazdealba quinoloneresistancereversionbytargetingthesosresponse AT mramosguelfo quinoloneresistancereversionbytargetingthesosresponse AT fdocoboperez quinoloneresistancereversionbytargetingthesosresponse AT jrodriguezbeltran quinoloneresistancereversionbytargetingthesosresponse AT jblazquez quinoloneresistancereversionbytargetingthesosresponse AT apascual quinoloneresistancereversionbytargetingthesosresponse AT jmrodriguezmartinez quinoloneresistancereversionbytargetingthesosresponse
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Quinolone Resistance Reversion by Targeting the SOS Response

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