The anti-platelet drug ticlopidine inhibits FapC fibrillation and biofilm production: Highlighting its antibiotic activity

Mitra Pirhaghi, Zahra Najarzadeh, Faezeh Moosavi-Movahedi, Mahshid Shafizadeh, Fatemeh Mamashli, Deyhim Atarod, Atiyeh Ghasemi, Dina Morshedi, Ali Akbar Meratan, Daniel E Otzen, Ali Akbar Saboury

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Multidrug resistance of bacteria and persistent infections related to biofilms, as well as the low availability of new antibacterial drugs, make it urgent to develop new antibiotics. Here, we evaluate the antibacterial and anti-biofilm properties of ticlopidine (TP), an anti-platelet aggregation drug, TP showed antibacterial activity against both gram-positive (MRSA) and gram-negative (E. coli, and P. aeruginosa) bacteria over a long treatment period. TP significantly reduced the survival of gram-negative bacteria in human blood though impact on gram-positives was more limited. TP may cause death in MRSA by inhibiting staphyloxanthin pigment synthesis, leading to oxidative stress, while scanning electron microscopy imaging indicate a loss of membrane integrity, damage, and consequent death due to lysis in gram-negative bacteria. TP showed good anti-biofilm activity against P. aeruginosa and MRSA, and a stronger biofilm degradation activity on P. aeruginosa compared to MRSA. Measuring fluorescence of the amyloid-reporter Thioflavin T (ThT) in biofilm implicated inhibition of amyloid formation as part of TP activity. This was confirmed by assays on the purified protein in P. aeruginosa, FapC, whose fibrillation kinetics was inhibited by TP. TP prolonged the lag phase of aggregation and reduced the subsequent growth rate and prolonging the lag phase to very long times provides ample opportunity to exert TP's antibacterial effect. We conclude that TP shows activity as an antibiotic against both gram-positive and gram-negative bacteria thanks to a broad range of activities, targeting bacterial metabolic processes, cellular structures and the biofilm matrix.

Original languageEnglish
Article number140883
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1871
Issue2
Number of pages14
ISSN1570-9639
DOIs
Publication statusPublished - Feb 2023

Keywords

  • Amyloid fibrillation
  • Antibacterial
  • Bacterial biofilm
  • FapC
  • Ticlopidine
  • Biofilms
  • Escherichia coli
  • Gram-Negative Bacteria/physiology
  • Humans
  • Gram-Positive Bacteria
  • Anti-Bacterial Agents/pharmacology

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