High-throughput profiling of drug interactions in Gram-positive bacteria

• DOI: 10.1101/2022.12.23.521747
• Publication Date: 2022-12-24T04:55:22Z
• Authors: Elisabetta Cacace; Vladislav Kim; Michael Knopp; Manuela Tietgen; Amber Brauer-Nikonow; Kemal Inecik; André Mateus; Alessio Milanese; Marita Torrissen ...; Karin Mitosch; Joel Selkrig; Ana Rita Brochado; Oscar P. Kuipers; Morten Kjos; Georg Zeller; Mikhail M. Savitski; Stephan Göttig; Wolfgang Huber; Athanasios Typas
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

Abstract Drug combinations present a powerful strategy to tackle antimicrobial resistance, but have not been systematically tested in many bacterial species. Here, we used an automated high-throughput setup profile ∼ 8000 between 65 antibacterial drugs three Gram-positive species: the model species, Bacillus subtilis and two prominent pathogens, Staphylococcus aureus Streptococcus pneumoniae . Thereby, recapitulate previously known drug interactions, also identify ten times more interactions than reported pathogen S. , including synergies that were effective multi-drug resistant clinical isolates vitro vivo Interactions largely species-specific mostly synergistic for targeting same cellular process, as observed Gram-negative species 1 Yet, dominating are clearly distinct driven by different bottlenecks uptake vulnerabilities of their cell surface structures. To further explore commonly prescribed non-antibiotic with antibiotics, 2728 such detecting plethora unexpected antagonisms could compromise efficacy treatments age polypharmacy. We uncovered even antagonisms, some which demonstrate against isolates. Among them, showed antiaggregant ticagrelor interferes purine metabolism changes charge aureus, leading strong cationic antibiotics. Overall, this exemplifies untapped potential approved non-antibacterial be repurposed antibiotic adjuvants. All data can browsed through interactive interface ( https://apps.embl.de/combact/ ).