Thesis, COLLÉGIALITÉ

Abstract

Antimicrobial resistance accounts for an annual mortality of 1.27 million deaths and this number is estimated to increase to 10 million deaths per year by 2050. One pathogen of particular concern is methicillin-resistant Staphylococcus aureus which can induce life threatening diseases such as infective endocarditis, pneumonia, or osteomyelitis. The high mortality rate related to infection with Staphylococcus aureus strains that are resistant to last-resort antibiotics including vancomycin and daptomycin, urges for novel treatment options. Recently, the antiplatelet drug ticagrelor was found to possess bactericidal properties against Gram-positive and resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. The antibacterial properties of ticagrelor were corroborated by several clinical studies, describing a reduced infection risk in patients treated with ticagrelor compared to other P2Y12 antagonists. This thesis aims to characterize cross-resistance of ticagrelor with conventional anti-methicillin-resistant Staphylococcus aureus antibiotics vancomycin and daptomycin, as well as the combinatory antibacterial effect of ticagrelor with these last-resort antibiotics against antibiotic-resistant Staphylococcus aureus strains. We show no cross-resistance between ticagrelor and the last-resort antibiotic vancomycin. In contrast, the daptomycin-resistant SADR-2 strain containing mutations in genes encoding for ClpPG94D and RpoBA477D was resistant to ticagrelor, while in vitro-generated ticagrelor-resistant strains remained sensitive to daptomycin. Notably, ticagrelor showed additive antibacterial effects when combined with last-resort antibiotics vancomycin and daptomycin against methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. Our results highlight the potential of combining ticagrelor with conventionally used antibiotics in a clinical setting against difficult to treat Staphylococcus aureus infections. Furthermore, ticagrelor might prove beneficial compared to other P2Y12 inhibitors in the prevention of Staphylococcus aureus infections in patients that are at increased risk of developing infections and who need antiplatelet treatment.