Commonly prescribed medicines antagonise anti-MRSA antibiotics and select for resistance.

Many commonly prescribed non-antibiotic medicines have off-target antimicrobial activity, yet their impact on antibiotic efficacy remains poorly understood. In this study, we investigated eight widely used UK prescription medicines and identified simvastatin, amlodipine and fluoxetine as growth inhibitory towards methicillin-resistant Staphylococcus aureus. These drugs disrupt bacterial membranes, with amlodipine and fluoxetine also triggering stress responses linked to cell wall and membrane damage. Further mechanistic analysis using transposon mutant screening revealed that simvastatin impairs cell wall synthesis by inhibiting the mevalonate pathway. Notably, checkerboard assays demonstrated antagonistic interactions: simvastatin reduced the efficacy of β-lactams and vancomycin, amlodipine with vancomycin and daptomycin and fluoxetine with vancomycin activity. Prolonged exposure to these drugs also accelerated resistance development to vancomycin and daptomycin. Together, these findings underscore the potential for commonly prescribed non-antibiotic medicines to undermine antibiotic therapy, warranting further study given the rising S. aureus treatment failures.