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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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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. |
format | Online Article Text |
id | pubmed-7787680 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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