Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers

Matthew P. McCusker; Daniela Alves Ferreira; Donal Cooney; Bruno Martins Alves; Seámus Fanning; Jean Marie Pagès; Marta Martins; Anne Davin-Regli

doi:10.1016/j.jgar.2018.10.009

Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers

Matthew P. McCusker, Daniela Alves Ferreira, Donal Cooney, Bruno Martins Alves, Seámus Fanning, Jean Marie Pagès, Marta Martins, Anne Davin-Regli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

Objective: The main focus of this study was to evaluate the antimicrobial susceptibility profiles of a number of human clinical isolates of Enterobacter aerogenes isolates and to explore the effects of selected chemosensitisers on reversal of the resistant phenotype of these isolates.

Methods: This study design was accomplished by: (i) characterising several multidrug-resistant (MDR) E. aerogenes clinical isolates; (ii) evaluating the contribution of target gene mutations to the resistance phenotype, focusing on fluoroquinolones and chloramphenicol only; (iii) evaluating the contribution of membrane permeability and efflux to the MDR phenotype; (iv) assessing the combined action of selected antimicrobials and chemosensitisers in order to identify combinations with synergistic effects able to reduce the minimum inhibitory concentration (MIC); and (v) understanding how these combinations can modulate the permeability or efflux of these isolates.

Results: Resistance to ciprofloxacin could not be totally reversed owing to pre-existing mutations in target genes. Chloramphenicol susceptibility was efficiently restored by the addition of the selected chemosensitisers. From the modulation kinetics it was clear that phenothiazines were able to increase the accumulation of Hoechst dye.

Conclusions: Modulation of permeability and efflux in the presence of chemosensitisers can help us to propose more appropriate chemotherapeutic combinations that can set the model to be used in the treatment of these and other MDR infections.

Original language	English
Pages (from-to)	187-198
Number of pages	12
Journal	Journal of Global Antimicrobial Resistance
Volume	16
Early online date	08 Feb 2019
DOIs	https://doi.org/10.1016/j.jgar.2018.10.009
Publication status	Published - Mar 2019
Externally published	Yes

Bibliographical note

Funding Information:
The research leading to the results discussed here was conducted as part of the Translocation Consortium (http://www.translocation.eu) and has received support from the Innovative Medicines joint Undertaking [grant agreement no. 115525], resources which are composed of financial contribution from the European Union's Seventh Framework Programme [FP/2007-2013] and EFPIA companies in kind contributions. This work was also partly supported by the Agence Nationale de la Recherche (ANR, France) [grant ANR-11-BS07-019-0]. MPM was partially supported by the Dawn Farm Foods Newman Fellowship in Food Safety. MM was partially supported by the Vétoquinol SA Newman Fellowship in Food Safety.

Funding Information:
The research leading to the results discussed here was conducted as part of the Translocation Consortium ( http://www.translocation.eu ) and has received support from the Innovative Medicines joint Undertaking [grant agreement no. 115525 ], resources which are composed of financial contribution from the European Union’s Seventh Framework Programme [ FP/2007-2013 ] and EFPIA companies in kind contributions. This work was also partly supported by the Agence Nationale de la Recherche (ANR, France) [grant ANR-11-BS07-019-0 ]. MPM was partially supported by the Dawn Farm Foods Newman Fellowship in Food Safety . MM was partially supported by the Vétoquinol SA Newman Fellowship in Food Safety .

Publisher Copyright:
© 2018 International Society for Chemotherapy of Infection and Cancer

Keywords

Chemosensitisers
Combination therapy
Efflux pump
Fluoroquinolones
Multidrug resistance
Permeability

ASJC Scopus subject areas

Microbiology
Immunology and Allergy
Immunology
Microbiology (medical)

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Cite this

McCusker, M. P., Alves Ferreira, D., Cooney, D., Martins Alves, B., Fanning, S., Pagès, J. M., Martins, M., & Davin-Regli, A. (2019). Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers. Journal of Global Antimicrobial Resistance, 16, 187-198. https://doi.org/10.1016/j.jgar.2018.10.009

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title = "Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers",

abstract = "Objective: The main focus of this study was to evaluate the antimicrobial susceptibility profiles of a number of human clinical isolates of Enterobacter aerogenes isolates and to explore the effects of selected chemosensitisers on reversal of the resistant phenotype of these isolates. Methods: This study design was accomplished by: (i) characterising several multidrug-resistant (MDR) E. aerogenes clinical isolates; (ii) evaluating the contribution of target gene mutations to the resistance phenotype, focusing on fluoroquinolones and chloramphenicol only; (iii) evaluating the contribution of membrane permeability and efflux to the MDR phenotype; (iv) assessing the combined action of selected antimicrobials and chemosensitisers in order to identify combinations with synergistic effects able to reduce the minimum inhibitory concentration (MIC); and (v) understanding how these combinations can modulate the permeability or efflux of these isolates. Results: Resistance to ciprofloxacin could not be totally reversed owing to pre-existing mutations in target genes. Chloramphenicol susceptibility was efficiently restored by the addition of the selected chemosensitisers. From the modulation kinetics it was clear that phenothiazines were able to increase the accumulation of Hoechst dye. Conclusions: Modulation of permeability and efflux in the presence of chemosensitisers can help us to propose more appropriate chemotherapeutic combinations that can set the model to be used in the treatment of these and other MDR infections.",

keywords = "Chemosensitisers, Combination therapy, Efflux pump, Fluoroquinolones, Multidrug resistance, Permeability",

author = "McCusker, {Matthew P.} and {Alves Ferreira}, Daniela and Donal Cooney and {Martins Alves}, Bruno and Se{\'a}mus Fanning and Pag{\`e}s, {Jean Marie} and Marta Martins and Anne Davin-Regli",

note = "Funding Information: The research leading to the results discussed here was conducted as part of the Translocation Consortium (http://www.translocation.eu) and has received support from the Innovative Medicines joint Undertaking [grant agreement no. 115525], resources which are composed of financial contribution from the European Union's Seventh Framework Programme [FP/2007-2013] and EFPIA companies in kind contributions. This work was also partly supported by the Agence Nationale de la Recherche (ANR, France) [grant ANR-11-BS07-019-0]. MPM was partially supported by the Dawn Farm Foods Newman Fellowship in Food Safety. MM was partially supported by the V{\'e}toquinol SA Newman Fellowship in Food Safety. Funding Information: The research leading to the results discussed here was conducted as part of the Translocation Consortium ( http://www.translocation.eu ) and has received support from the Innovative Medicines joint Undertaking [grant agreement no. 115525 ], resources which are composed of financial contribution from the European Union{\textquoteright}s Seventh Framework Programme [ FP/2007-2013 ] and EFPIA companies in kind contributions. This work was also partly supported by the Agence Nationale de la Recherche (ANR, France) [grant ANR-11-BS07-019-0 ]. MPM was partially supported by the Dawn Farm Foods Newman Fellowship in Food Safety . MM was partially supported by the V{\'e}toquinol SA Newman Fellowship in Food Safety . Publisher Copyright: {\textcopyright} 2018 International Society for Chemotherapy of Infection and Cancer",

year = "2019",

month = mar,

doi = "10.1016/j.jgar.2018.10.009",

language = "English",

volume = "16",

pages = "187--198",

journal = "Journal of Global Antimicrobial Resistance",

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McCusker, MP, Alves Ferreira, D, Cooney, D, Martins Alves, B, Fanning, S, Pagès, JM, Martins, M & Davin-Regli, A 2019, 'Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers', Journal of Global Antimicrobial Resistance, vol. 16, pp. 187-198. https://doi.org/10.1016/j.jgar.2018.10.009

TY - JOUR

T1 - Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers

AU - McCusker, Matthew P.

AU - Alves Ferreira, Daniela

AU - Cooney, Donal

AU - Martins Alves, Bruno

AU - Fanning, Seámus

AU - Pagès, Jean Marie

AU - Martins, Marta

AU - Davin-Regli, Anne

N1 - Funding Information: The research leading to the results discussed here was conducted as part of the Translocation Consortium (http://www.translocation.eu) and has received support from the Innovative Medicines joint Undertaking [grant agreement no. 115525], resources which are composed of financial contribution from the European Union's Seventh Framework Programme [FP/2007-2013] and EFPIA companies in kind contributions. This work was also partly supported by the Agence Nationale de la Recherche (ANR, France) [grant ANR-11-BS07-019-0]. MPM was partially supported by the Dawn Farm Foods Newman Fellowship in Food Safety. MM was partially supported by the Vétoquinol SA Newman Fellowship in Food Safety. Funding Information: The research leading to the results discussed here was conducted as part of the Translocation Consortium ( http://www.translocation.eu ) and has received support from the Innovative Medicines joint Undertaking [grant agreement no. 115525 ], resources which are composed of financial contribution from the European Union’s Seventh Framework Programme [ FP/2007-2013 ] and EFPIA companies in kind contributions. This work was also partly supported by the Agence Nationale de la Recherche (ANR, France) [grant ANR-11-BS07-019-0 ]. MPM was partially supported by the Dawn Farm Foods Newman Fellowship in Food Safety . MM was partially supported by the Vétoquinol SA Newman Fellowship in Food Safety . Publisher Copyright: © 2018 International Society for Chemotherapy of Infection and Cancer

PY - 2019/3

Y1 - 2019/3

N2 - Objective: The main focus of this study was to evaluate the antimicrobial susceptibility profiles of a number of human clinical isolates of Enterobacter aerogenes isolates and to explore the effects of selected chemosensitisers on reversal of the resistant phenotype of these isolates. Methods: This study design was accomplished by: (i) characterising several multidrug-resistant (MDR) E. aerogenes clinical isolates; (ii) evaluating the contribution of target gene mutations to the resistance phenotype, focusing on fluoroquinolones and chloramphenicol only; (iii) evaluating the contribution of membrane permeability and efflux to the MDR phenotype; (iv) assessing the combined action of selected antimicrobials and chemosensitisers in order to identify combinations with synergistic effects able to reduce the minimum inhibitory concentration (MIC); and (v) understanding how these combinations can modulate the permeability or efflux of these isolates. Results: Resistance to ciprofloxacin could not be totally reversed owing to pre-existing mutations in target genes. Chloramphenicol susceptibility was efficiently restored by the addition of the selected chemosensitisers. From the modulation kinetics it was clear that phenothiazines were able to increase the accumulation of Hoechst dye. Conclusions: Modulation of permeability and efflux in the presence of chemosensitisers can help us to propose more appropriate chemotherapeutic combinations that can set the model to be used in the treatment of these and other MDR infections.

AB - Objective: The main focus of this study was to evaluate the antimicrobial susceptibility profiles of a number of human clinical isolates of Enterobacter aerogenes isolates and to explore the effects of selected chemosensitisers on reversal of the resistant phenotype of these isolates. Methods: This study design was accomplished by: (i) characterising several multidrug-resistant (MDR) E. aerogenes clinical isolates; (ii) evaluating the contribution of target gene mutations to the resistance phenotype, focusing on fluoroquinolones and chloramphenicol only; (iii) evaluating the contribution of membrane permeability and efflux to the MDR phenotype; (iv) assessing the combined action of selected antimicrobials and chemosensitisers in order to identify combinations with synergistic effects able to reduce the minimum inhibitory concentration (MIC); and (v) understanding how these combinations can modulate the permeability or efflux of these isolates. Results: Resistance to ciprofloxacin could not be totally reversed owing to pre-existing mutations in target genes. Chloramphenicol susceptibility was efficiently restored by the addition of the selected chemosensitisers. From the modulation kinetics it was clear that phenothiazines were able to increase the accumulation of Hoechst dye. Conclusions: Modulation of permeability and efflux in the presence of chemosensitisers can help us to propose more appropriate chemotherapeutic combinations that can set the model to be used in the treatment of these and other MDR infections.

KW - Chemosensitisers

KW - Combination therapy

KW - Efflux pump

KW - Fluoroquinolones

KW - Multidrug resistance

KW - Permeability

U2 - 10.1016/j.jgar.2018.10.009

DO - 10.1016/j.jgar.2018.10.009

M3 - Article

C2 - 30321623

AN - SCOPUS:85061152791

SN - 2213-7165

VL - 16

SP - 187

EP - 198

JO - Journal of Global Antimicrobial Resistance

JF - Journal of Global Antimicrobial Resistance

ER -

Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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