Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria.
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Authors
Donnert, MoniqueElsheikh, Sarah
Arce-Rodriguez, Alejandro
Pawar, Vinay
Braubach, Peter
Jonigk, Danny
Haverich, Axel
Weiss, Siegfried
Müsken, Mathias
Häussler, Susanne
Issue Date
2020-12-22
Metadata
Show full item recordAbstract
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.Citation
PLoS Pathog. 2020 Dec 22;16(12):e1009126. doi: 10.1371/journal.ppat.1009126.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
PLOSJournal
PLoS pathogensPubMed ID
33351859Type
ArticleLanguage
enEISSN
1553-7374ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1009126
Scopus Count
The following license files are associated with this item:
- Creative Commons
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