Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success

Significance Persisters represent a bacterial subpopulation that survive high antibiotic concentrations without being resistant. Their role in clinics in persistent infections and their molecular and functional landscape is not fully established. Staphylococcus aureus is a pathobiont that causes severe invasive infections often difficult to treat. Here, we assessed S. aureus recovered directly from persistent infections and show that host-mediated stress and antibiotic exposure promoted persister formation. Using a multiomics approach and enrichment of persisters, we were able to draw a molecular atlas of persisters, to correlate accumulation of insoluble proteins and ATP depletion with dormancy and persistence. Our results give insights into the molecular profile of bacterial persisters and provide a guide for therapy optimization for persistent S. aureus infections.