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CME Evaluation

Oral Communication Session

Vascular Biology, Blood Cells, and Immunothrombosis

Session: Infection and immunothrombosis

OC 67.1 - Ticagrelor targets the cell envelope of Gram-positive bacteria and retains activity against multidrug resistant Staphylococcus aureus

Tuesday, June 25, 2024
14:45 – 15:00 ICT
Room: 210 A-D
Background: Infection with multidrug resistant bacteria poses a major health care problem which urges the need for novel treatment options. In addition to its potent antiplatelet properties, we found that the P2Y12 antagonist ticagrelor has antibacterial activity against Gram-positive bacteria, including resistant strains. Our findings were corroborated by several studies in cardiovascular patients who had a lower risk of Staphylococcus aureus bacteremia when receiving ticagrelor instead of clopidogrel.

Aims: To assess the mode of action of ticagrelor on multidrug resistant staphylococci.

Methods: We used Bacillus subtilis as a model of Gram-positive bacteria to conduct an antibiotic stress induced bioreporter assay, membrane potential measurements and growth curve analyses before studying methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains (VISA). We then performed whole genome sequencing and lipodomics of in vitro-generated ticagrelor-resistant MRSA clones. Cross-resistance and interactions of ticagrelor with common antibiotics used against MRSA, daptomycin and vancomycin were analyzed.

Results: An antibiotic stress induced bioreporter assay in Bacillus subtilis revealed that ticagrelor induces pathways essential for maintaining integrity of the bacterial cytoplasmic membrane. Ticagrelor, at subinhibitory dose, caused bacterial membrane depolarization in Bacillus subtilis and MRSA, and it increased surface hydrophobicity. At bactericidal concentration, ticagrelor affected membrane integrity, with an uptake of membrane impermeable dye and the formation of lipid aggregates. Ticagrelor resistant MRSA clones had mutations in genes encoding for ClpP, ClpX and YjbH, all component of the ClpXP protease. Lipidomic analysis of these clones showed lower cardiolipin and 14:0 fatty acyl chain-bearing phosphatidyl glycerol and diacylglycerol content. The addition of exogeneous cardiolipin, phosphatidylglycerol, or diacylglycerol quenched the antibacterial properties of ticagrelor. Finally, no cross-resistance was observed between ticagrelor, daptomycin or vancomycin resistant Staphylococcus aureus strains.

Conclusion(s): Our study demonstrates that ticagrelor targets multiple lipids in the cytoplasmic membrane of Gram-positive bacteria, thereby retaining activity against multidrug resistant staphylococci including daptomycin, and vancomycin resistant strains.