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

Monique Donnert, Sarah Elsheikh, Alejandro Arce-Rodriguez, Vinay Pawar, Peter Braubach, Danny Jonigk, Axel Haverich, Siegfried Weiss, Mathias Müsken, Susanne Häussler

Abstract

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.

Original languageEnglish
JournalPLoS pathogens
Volume16
Issue number12
Pages (from-to)e1009126
ISSN1553-7366
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Animals
  • Biofilms/drug effects
  • Drug Tolerance/physiology
  • Energy Metabolism/drug effects
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Promethazine/pharmacology
  • Pseudomonas Infections
  • Pseudomonas aeruginosa/drug effects

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