Gram-positive bacteria; drug discovery; drug interactions; platelets
Abstract :
[en] Infections with multidrug-resistant bacteria pose a major healthcare problem which urges the need for novel treatment options. Besides its potent antiplatelet properties, ticagrelor has antibacterial activity against Gram-positive bacteria, including methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). Several retrospective studies in cardiovascular patients support an antibacterial effect of this drug which is not related to its antiplatelet activity. We investigated the mechanism of action of ticagrelor in Staphylococcus aureus and model Bacillus subtilis, and assessed cross-resistance with two conventional anti-MRSA antibiotics, vancomycin and daptomycin. Bacillus subtilis bioreporter strains revealed ticagrelor-induced cell envelope-related stress responses. Sub-inhibitory drug concentrations caused membrane depolarization, impaired positioning of both the peripheral membrane protein MinD and the peptidoglycan precursor lipid II, and it affected cell shape. At the MIC, ticagrelor destroyed membrane integrity, indicated by the influx of membrane impermeable dyes, and lipid aggregate formation. Whole-genome sequencing of in vitro-generated ticagrelor-resistant MRSA clones revealed mutations in genes encoding ClpP, ClpX, and YjbH. Lipidomic analysis of resistant clones displayed changes in levels of the most abundant lipids of the Staphylococcus aureus membrane, for example, cardiolipins, phosphatidylglycerols, and diacylglycerols. Exogeneous cardiolipin, phosphatidylglycerol, or diacylglycerol antagonized the antibacterial properties of ticagrelor. Ticagrelor enhanced MRSA growth inhibition and killing by vancomycin and daptomycin in both exponential and stationary phases. Finally, no cross-resistance was observed between ticagrelor and daptomycin, or vancomycin. 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.IMPORTANCEInfections with multidrug-resistant bacteria pose a major healthcare problem with an urgent need for novel treatment options. The antiplatelet drug ticagrelor possesses antibacterial activity against Gram-positive bacteria including methicillin-resistant and vancomycin-resistant Staphylococcus aureus strains. We report a unique, dose-dependent, antibacterial mechanism of action of ticagrelor, which alters the properties and integrity of the bacterial cytoplasmic membrane. Ticagrelor retains activity against multidrug-resistant staphylococci, including isolates carrying the most common in vivo selected daptomycin resistance mutations and vancomycin-intermediate Staphylococcus aureus. Our data support the use of ticagrelor as adjunct therapy against multidrug-resistant strains. Because of the presence of multiple non-protein targets of this drug within the bacterial membrane, resistance development is expected to be slow. All these findings corroborate the accumulating observational clinical evidence for a beneficial anti-bacterial effect of ticagrelor in cardiovascular patients in need of such treatment.
Jacques, Nicolas ; Université de Liège - ULiège > GIGA > GIGA Cardiovascular Sciences - Cardiology
Esquembre, Lidia Alejo; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, Germany
Schneider, Dana C; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, Germany
Straetener, Jan; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, Germany
Henriksen, Camilla; Department of Veterinary and Animal Sciences, Faculty of Health and Medical sciences, University of Copenhagen, Copenhagen, Denmark
MUSUMECI, Lucia ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chirurgie cardio-vasculaire et thoracique
Putters, Florence ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Ferreira Melo, Sofia ; Université de Liège - ULiège > GIGA > GIGA Metabolism & Cardiovascular Biology - Cardiology
Sánchez-López, Elena; Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands
Giera, Martin; Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands
Penoy, Noémie ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Piel, Géraldine ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Verlaine, Olivier; Bacterial physiology and genetics-Centre d'Ingénierie des Protéines-Integrative Biological Sciences, University of Liège > Department of Life Sciences
Amoroso, Ana; Bacterial physiology and genetics-Centre d'Ingénierie des Protéines-Integrative Biological Sciences, Department of Life Sciences, University of Liège, Liège, Belgium
Joris, Bernard; Bacterial physiology and genetics-Centre d'Ingénierie des Protéines-Integrative Biological Sciences, Department of Life Sciences, University of Liège, Liège, Belgium
Slavetinsky, Christoph J ; Pediatric Surgery and Urology, University Children's Hospital Tübingen, University of Tübingen, Tübingen, Germany ; German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany ; Cluster of Excellence "Controlling Microbes to Fight Infections (CMFI)", University of Tübingen, Tübingen, Germany
Goffin, Eric ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie
Frees, Dorte ; Department of Veterinary and Animal Sciences, Faculty of Health and Medical sciences, University of Copenhagen, Copenhagen, Denmark
Brötz-Oesterhelt, Heike ; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, Germany ; German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany ; Cluster of Excellence "Controlling Microbes to Fight Infections (CMFI)", University of Tübingen, Tübingen, Germany
Lancellotti, Patrizio ; Université de Liège - ULiège > Département des sciences cliniques > Cardiologie - Pathologie spéciale et réhabilitation
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