Article, 2022

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

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, ISSN 1878-2434, 1570-9639, 1878-1454, Volume 1871, 2, Page 140883, 10.1016/j.bbapap.2022.140883

Contributors

Pirhaghi, Mitra [1] [2] Najarzadeh, Zahra 0000-0002-0044-7537 [1] Moosavi-Movahedi, Faezeh 0000-0001-9378-3232 [2] Shafizadeh, Mahshid [2] Mamashli, Fatemeh 0000-0002-7429-6639 [2] Atarod, Deyhim [2] Ghasemi, Atiyeh [2] Morshedi, Dina 0000-0002-0751-8772 [3] Meratan, Ali Akbar 0000-0002-1428-3254 [4] Otzen, Daniel Erik 0000-0002-2918-8989 [1] Saboury, Ali Akbar 0000-0003-0604-9465 (Corresponding author) [2]

Affiliations

  1. [1] Aarhus University
    2. [NORA names: AU Aarhus University; University; Denmark; Europe, EU; Nordic; OECD];
  2. [2] University of Tehran
    3. [NORA names: Iran; Asia, Middle East];
  3. [3] National Institute of Genetic Engineering and Biotechnology
    4. [NORA names: Iran; Asia, Middle East];
  4. [4] Institute for Advanced Studies in Basic Sciences
    5. [NORA names: Iran; Asia, Middle East]

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.

Keywords

FapC, FapC fibrillation, Gram-negative, Gram-negative bacteria, Gram-positive, MRSA, Multidrug, P. aeruginosa, TP activity, ThT, activity, aggregation, aggregation drugs, amyloid formation, anti-biofilm activity, anti-biofilm properties, anti-platelet aggregation drugs, antibacterial activity, antibacterial drugs, antibacterial effect, antibiotic activity, antibiotics, assay, availability, bacteria, bacterial metabolic processes, biofilm, biofilm degradation activity, biofilm matrix, biofilm production, blood, cellular structure, damage, death, degradation activity, drug, effect, electron microscopy images, fibrillation, fibrillation kinetics, fluorescence, formation, growth, growth rate, human blood, images, impact, inhibition, inhibition of amyloid formation, integration, kinetics, long time, longer treatment period, loss, loss of membrane integrity, low availability, lysis, matrix, measuring fluorescence, membrane integrity, metabolic processes, microscopy images, multidrug resistance, multidrug resistance of bacteria, oxidative stress, period, phase, phase of aggregation, pigment synthesis, process, production, protein, purified protein, rate, resistance of bacteria, scanning electron microscopy images, stress, structure, survival, survival of Gram-negative bacteria, synthesis, thanks, thioflavin T, ticlopidine, time, treatment period

Funders

  • Lundbeck Foundation
  • Iran National Science Foundation

Data Provider: Digital Science

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