Repurposed membrane-targeting RS17053 eradicates MRSA persisters and enhances aminoglycoside killing

The rapid rise of methicillin-resistant Staphylococcus aureus (MRSA) and its ability to form antibiotic-tolerant persisters pose a major challenge to antimicrobial therapy. These metabolically dormant cells survive antibiotic exposure without genetic resistance, driving chronic and relapsing infections. Here, we characterize RS17053-a selective α1A-adrenoceptor antagonist- as a membrane-active compound with potent activity against both antibiotic-resistant and antibiotic-tolerant S. aureus. RS17053 disrupts bacterial phospholipid bilayers, causing membrane permeabilization, intracellular leakage, accumulation of reactive oxygen species, and subsequent cell death, while exhibiting minimal cytotoxicity toward mammalian cells. The compound shows no detectable resistance after prolonged exposure and synergistically enhances aminoglycoside potency by promoting drug uptake into MRSA persisters. In a Caenorhabditis elegans infection model, RS17053 protects hosts from lethal MRSA challenge. Collectively, these findings support RS17053 as an antimicrobial lead compound suitable for repurposing as both a direct-acting antimicrobial and an adjuvant to aminoglycosides for treating persistent MRSA infections.