Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE

V. Baldelli, F. D’Angelo, V. Pavoncello, E.V. Fiscarelli, P. Visca, G. Rampioni, L. Leoni

Research output: Contribution to journalArticlepeer-review

Abstract

The ability of the bacterial pathogen Pseudomonas aeruginosa to cause both chronic and acute infections mainly relies on its capacity to finely modulate the expression of virulence factors through a complex network of regulatory circuits, including the pqs quorum sensing (QS) system. While in most QS systems the signal molecule/receptor complexes act as global regulators that modulate the expression of QS-controlled genes, the main effector protein of the pqs system is PqsE. This protein is involved in the synthesis of the QS signal molecules 2-alkyl-4(1H)-quinolones (AQs), but it also modulates the expression of genes involved in virulence factors production and biofilm formation via AQ-independent pathway(s). P. aeruginosa pqsE mutants disclose attenuated virulence in plant and animal infection models, hence PqsE is considered a good target for the development of antivirulence drugs against P. aeruginosa. In this study, the negative regulation exerted by PqsE on its own transcription has been exploited to develop a screening system for the identification of PqsE inhibitors in a library of FDA-approved drugs. This led to the identification of nitrofurazone and erythromycin estolate, two antibiotic compounds that reduce the expression of PqsE-dependent virulence traits and biofilm formation in the model strain P. aeruginosa PAO1 at concentrations far below those affecting the bacterial growth rate. Notably, both drugs reduce the production of the PqsE-controlled virulence factor pyocyanin also in P. aeruginosa strains isolated from cystic fibrosis patients, and do not antagonize the activity of antibiotics commonly used to treat P. aeruginosa infection. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Original languageEnglish
Pages (from-to)652-668
Number of pages17
JournalVirulence
Volume11
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • antivirulence strategy
  • erythromycin estolate
  • nitrofurazone
  • PqsE
  • Pseudomonas aeruginosa
  • quorum sensing inhibition
  • screening
  • ampicillin
  • antibiotic agent
  • bacterial protein
  • erythromycin
  • isopropyl thiogalactoside
  • nitrofural
  • plasmid DNA
  • protein PqsE
  • pyocyanine
  • tetracycline
  • unclassified drug
  • virulence factor
  • antiinfective agent
  • Article
  • bacterial growth
  • bacterial infection
  • bacterial strain
  • bacterial virulence
  • bacterium identification
  • bacterium isolation
  • biofilm
  • bioluminescence
  • cell density
  • colony forming unit
  • cystic fibrosis
  • EC50
  • Escherichia coli
  • gene amplification
  • gene expression
  • IC50
  • minimum bactericidal concentration
  • minimum inhibitory concentration
  • nonhuman
  • organisms by carbon source
  • phenotype
  • quorum sensing
  • biosynthesis
  • drug approval
  • drug development
  • drug effect
  • genetics
  • growth, development and aging
  • human
  • microbiology
  • pathogenicity
  • signal transduction
  • virulence
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Biofilms
  • Cystic Fibrosis
  • Drug Approval
  • Drug Discovery
  • Humans
  • Pyocyanine
  • Quorum Sensing
  • Signal Transduction
  • Virulence
  • Virulence Factors

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