Repurposing nifedipine as a dual-function adjuvant: potentiating gentamicin activity and disrupting biofilm formation in methicillin-resistant Staphylococcus aureus.

The diminishing efficacy of gentamicin against methicillin-resistant Staphylococcus aureus (MRSA) necessitates novel adjuvant strategies, prompting our investigation into repurposing the calcium channel blocker nifedipine. Here, we demonstrate that a sub-inhibitory concentration of nifedipine synergizes with gentamicin against MRSA T144, achieving rapid bactericidal killing within 2 h. Mechanistic studies reveal that nifedipine functions as a bacterial ion modulator, inhibiting Ca2+/Cl- influx and increasing membrane fluidity, which leads to membrane hyperpolarization, cytoplasmic acidification, and a significant enhancement of gentamicin uptake. Furthermore, nifedipine exhibits direct anti-virulence activity by enhancing membrane permeability, suppressing amyloid fibril formation, and potently inhibiting biofilm development. Collectively, our findings highlights the promising potential of nifedipine as a repurposed adjuvant against resilient MRSA infections.