Peptidylarginine deiminase inhibitors reduce bacterial membrane vesicle release and sensitize bacteria to antibiotic treatment

Uchini S Kosgodage, Paul Matewele, Giulia Mastroianni, Sigrun Lange, Igor Kraev, Dominik Brotherton, Brigitte Awamaria, Anthony P. Nicholas, Jameel Inal

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)
84 Downloads (Pure)

Abstract

Outer membrane and membrane vesicles (OMV/MV) are released from bacteria and participate in cell communication, biofilm formation and host-pathogen interactions. Peptidylarginine deiminases (PADs) are phylogenetically conserved enzymes that catalyze post-translational deimination/citrullination of proteins, causing structural and functional changes in target proteins. PADs also play major roles in the regulation of eukaryotic extracellular vesicle release. Here we show phylogenetically conserved pathways of PAD-mediated OMV/MV release in bacteria and describe deiminated/citrullinated proteins in E. coli and their derived OMV/MVs. Furthermore, we show that PAD inhibitors can be used to effectively reduce OMV/MV release, both in Gram-negative and Gram-positive bacteria. Importantly, this resulted in enhanced antibiotic sensitivity of both E. coli and S. aureus to a range of antibiotics tested. Our findings reveal novel strategies for applying pharmacological OMV/MV-inhibition to reduce antibiotic resistance.

Original languageEnglish
Article number227
JournalFrontiers Cellular and Infection Microbiology
Volume9
DOIs
Publication statusPublished - 27 Jun 2019

Keywords

  • Antibiotic sensitivity
  • Deimination/citrullination
  • E. coli VCS257
  • Outer-membrane vesicles (OMVs)
  • Peptidylarginine deiminase (PAD)
  • S. aureus subsp. aureus Rosenbach

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