Abstract Number: PB1397
Meeting: ISTH 2020 Congress
Background: Ticagrelor is an antiplatelet agent with both in vitro and in vivo bactericidal properties against gram-positive bacteria. The in vitro bactericidal activity of ticagrelor is direct, i.e. not mediated by platelets. Ticagrelor is the only antiplatelet drug with such dual action, which might make it superior to other available drugs through its ability to protect cardiovascular patients against thrombosis and potentially against gram-positive bacterial infections, e.g. infective endocarditis. While the mechanism of action of ticagrelor on platelets has been extensively studied, nothing is known about its direct action on gram-positive bacteria.
Aims: Our study aimed at unveiling the mechanism of action of ticagrelor against gram-positive bacteria.
Methods: A multistep mutant generation of Staphylococcus epidermidis was undertaken to isolate ticagrelor resistant clones. Whole Genome Sequencing (WGS) and comparative genomics analysis was performed on 10 clones and on wild type (wt) bacteria.
Membrane phospholipids of wt and mutant bacteria were analyzed by thin layer chromatography. Calcein-encapsulated unilamellar staphylococcus like-liposomes were prepared using the extrusion and ultracentrifugation method. Calcein release assay was performed to assess membrane bilayer disruption. Confocal microscopy was used to visualize ticagrelor effect on Bacillus subtilis, a gram-postive bacteria model.
Results: Three ticagrelor-resistant clones showed a non-synonymous mutation in cdsA, an essential gene for cell membrane phospholipid biosynthesis. Comparative lipid profiles of wt and resistant clones revealed increased cardiolipin content in the resistant clones compared to wt bacteria. In a calcein release assay ticagrelor was able to disrupt unilamellar staphylococcus like-liposomes. Confocal microscopy images of Bacillus subtilis treated with sub-inhibitory concentrations of ticagrelor showed a disruption of cytoplasmic membrane integrity already after 15 minutes of treatment.
Conclusions: Ticagrelor exerts bactericidal activity against gram-positive bacteria by disrupting their phospholipid membrane. As such, ticagrelor might also act as a sensitizing agent, by increasing the activity of other antibiotics.
To cite this abstract in AMA style:Musumeci L, Jacques N, Penoy N, Piel G, Goffin E, Pirotte B, Amoroso AM, Joris B, Verlaine O, Lancellotti P, Oury C. Ticagrelor Mechanism of Action on Gram-Positive Bacteria [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/ticagrelor-mechanism-of-action-on-gram-positive-bacteria/. Accessed January 21, 2022.
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