Nitrendipine synergizes with multiple antibiotics against methicillin-resistant Staphylococcus aureus by disrupting membrane homeostasis.

The emergence of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of innovative therapeutic strategies, including the repurposing of non-antibiotic drugs as antibiotic adjuvants. Here, we identified the FDA-approved dihydropyridine calcium channel blocker nitrendipine as a potent synergistic adjuvant that enhances the activity of multiple antibiotic classes against MRSA. Nitrendipine, which itself lacks intrinsic antibacterial activity (MIC > 128 mg/L), reduces the minimum inhibitory concentrations (MICs) of gentamicin, streptomycin, ampicillin, and colistin by 4- to 64-fold. Time-kill assays revealed that the nitrendipine-gentamicin combination achieves rapid, synergistic bactericidal activity within 4 h. This enhanced efficacy was recapitulated in an in vivo Galleria mellonella infection model. Mechanistically, nitrendipine intercalates into the bacterial membrane, leading to proton motive force dissipation and a reduction in negative surface charge. Furthermore, nitrendipine compromises membrane barrier function, inhibits efflux pump, and disrupts amyloid-like structures within the MRSA cell envelope, thereby promoting dose-dependent antibiotic uptake. Collectively, our findings identify nitrendipine as a promising antibiotic adjuvant that sensitizes MRSA to multiple antibiotic classes through a multifactorial mechanism, thereby supporting its repurposing for combination therapy against drug-resistant staphylococcal infections.