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Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria

Embedded in an extracellular matrix, biofilm-residing bacteria are protected from diverse physicochemical insults. In accordance, in the human host the general recalcitrance of biofilm-grown bacteria hinders successful eradication of chronic, biofilm-associated infections. In this study, we demonstr...

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Autores principales: Donnert, Monique, Elsheikh, Sarah, Arce-Rodriguez, Alejandro, Pawar, Vinay, Braubach, Peter, Jonigk, Danny, Haverich, Axel, Weiss, Siegfried, Müsken, Mathias, Häussler, Susanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787680/
https://www.ncbi.nlm.nih.gov/pubmed/33351859
http://dx.doi.org/10.1371/journal.ppat.1009126
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author Donnert, Monique
Elsheikh, Sarah
Arce-Rodriguez, Alejandro
Pawar, Vinay
Braubach, Peter
Jonigk, Danny
Haverich, Axel
Weiss, Siegfried
Müsken, Mathias
Häussler, Susanne
author_facet Donnert, Monique
Elsheikh, Sarah
Arce-Rodriguez, Alejandro
Pawar, Vinay
Braubach, Peter
Jonigk, Danny
Haverich, Axel
Weiss, Siegfried
Müsken, Mathias
Häussler, Susanne
author_sort Donnert, Monique
collection PubMed
description Embedded in an extracellular matrix, biofilm-residing bacteria are protected from diverse physicochemical insults. In accordance, in the human host the general recalcitrance of biofilm-grown bacteria hinders successful eradication of chronic, biofilm-associated infections. In this study, we demonstrate that upon addition of promethazine, an FDA approved drug, antibiotic tolerance of in vitro biofilm-grown bacteria can be abolished. We show that following the addition of promethazine, diverse antibiotics are capable of efficiently killing biofilm-residing cells at minimal inhibitory concentrations. Synergistic effects could also be observed in a murine in vivo model system. PMZ was shown to increase membrane potential and interfere with bacterial respiration. Of note, antibiotic killing activity was elevated when PMZ was added to cells grown under environmental conditions that induce low intracellular proton levels. Our results imply that biofilm-grown bacteria avoid antibiotic killing and become tolerant by counteracting intracellular alkalization through the adaptation of metabolic and transport functions. Abrogation of antibiotic tolerance by interfering with the cell’s bioenergetics promises to pave the way for successful eradication of biofilm-associated infections. Repurposing promethazine as a biofilm-sensitizing drug has the potential to accelerate the introduction of new treatments for recalcitrant, biofilm-associated infections into the clinic.
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spelling pubmed-77876802021-01-14 Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria Donnert, Monique Elsheikh, Sarah Arce-Rodriguez, Alejandro Pawar, Vinay Braubach, Peter Jonigk, Danny Haverich, Axel Weiss, Siegfried Müsken, Mathias Häussler, Susanne PLoS Pathog Research Article Embedded in an extracellular matrix, biofilm-residing bacteria are protected from diverse physicochemical insults. In accordance, in the human host the general recalcitrance of biofilm-grown bacteria hinders successful eradication of chronic, biofilm-associated infections. In this study, we demonstrate that upon addition of promethazine, an FDA approved drug, antibiotic tolerance of in vitro biofilm-grown bacteria can be abolished. We show that following the addition of promethazine, diverse antibiotics are capable of efficiently killing biofilm-residing cells at minimal inhibitory concentrations. Synergistic effects could also be observed in a murine in vivo model system. PMZ was shown to increase membrane potential and interfere with bacterial respiration. Of note, antibiotic killing activity was elevated when PMZ was added to cells grown under environmental conditions that induce low intracellular proton levels. Our results imply that biofilm-grown bacteria avoid antibiotic killing and become tolerant by counteracting intracellular alkalization through the adaptation of metabolic and transport functions. Abrogation of antibiotic tolerance by interfering with the cell’s bioenergetics promises to pave the way for successful eradication of biofilm-associated infections. Repurposing promethazine as a biofilm-sensitizing drug has the potential to accelerate the introduction of new treatments for recalcitrant, biofilm-associated infections into the clinic. Public Library of Science 2020-12-22 /pmc/articles/PMC7787680/ /pubmed/33351859 http://dx.doi.org/10.1371/journal.ppat.1009126 Text en © 2020 Donnert et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Donnert, Monique
Elsheikh, Sarah
Arce-Rodriguez, Alejandro
Pawar, Vinay
Braubach, Peter
Jonigk, Danny
Haverich, Axel
Weiss, Siegfried
Müsken, Mathias
Häussler, Susanne
Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria
title Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria
title_full Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria
title_fullStr Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria
title_full_unstemmed Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria
title_short Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria
title_sort targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787680/
https://www.ncbi.nlm.nih.gov/pubmed/33351859
http://dx.doi.org/10.1371/journal.ppat.1009126
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