Ticagrelor prevents infective endocarditis by mitigating Staphylococcus aureus virulence

Abstract

Infective endocarditis (IE) is a deadly disease mainly caused by the gram-positive and highly virulent bacteria Staphylococcus aureus (SA). Due to lack of efficacy of current antibiotic therapy, there is an urgent need to discover new strategies that could prevent this disease. To assess the ability of the antiplatelet drug ticagrelor, which also displays antibacterial activity against gram-positive bacteria, to prevent SAIE. We used a mouse model of infective endocarditis induced by a SAIE clinical isolate. Ticagrelor was administered orally at a conventional dosage (3 mg/kg, single dose) prior to infection and local histamine infusion on the aortic valve. Infected vegetation presence was determined by Gram staining on heart sections after three days. Antibacterial effect of ticagrelor at dosages equivalent to plasma levels achieved in patients (0.75–1.25 μg/mL) was assessed in vitro in human blood. Ticagrelor significantly prevented the formation of infected vegetation, with IE in only 14.3% of ticagrelor-treated mice ( n = 21) compared to 52.3% of vehicle-treated mice ( n = 37). Ex vivo ADP-induced platelet aggregation assays confirmed rapid reversibility of antiplatelet activity (4 hours), which made it unlikely that solely the antiplatelet effect would explain IE prevention by ticagrelor. Bacterial survival in blood was not diminished three days post-infection. We therefore assessed whether ticagrelor could affect bacterial virulence. We found that growing SA in the presence of 1.25 μg/mL ticagrelor inhibited a-toxin RNA expression and protein secretion, which was corroborated with drastically reduced hemolysis and platelet aggregation induced by bacterial supernatants. Ticagrelor-treated bacteria could no longer adhered to fibrinogen, and in whole blood perfusion experiments, flow-dependent bacterial adhesion on activated endothelial cells was severely impaired. Our study demonstrates the unprecedented ability of ticagrelor to prevent IE by a novel mechanism of directly mitigating bacterial virulence. Hence, clinical trials using ticagrelor as adjunct therapy to antibiotics in patients at risk for IE are warranted.