Repurposing Benzbromarone as an Antibacterial Agent against Gram-Positive Bacteria

The rise of antibiotic-resistant Gram-positive pathogens, particularly methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), presents a significant challenge in clinical settings. There is a critical need for new antibacterial agents to combat these resistant strains. Our study reveals that the uricosuric drug Benzbromarone (Benz) exhibits potent antibacterial activity against Gram-positive pathogens, with minimum inhibitory concentrations (MICs) ranging from 8 to 32 μg/mL and minimum bactericidal concentrations (MBCs) ranging from 32 to 128 μg/mL against clinical isolates of <i>S. aureus</i>, <i>S. epidermidis</i>, <i>Enterococcus faecalis</i>, and <i>Streptococcus agalactiae</i>. Furthermore, Benz significantly inhibits biofilm formation at subinhibitory concentrations and eradicates mature biofilms at higher concentrations. Benz also suppresses the hemolytic activity of <i>S. aureus</i>, indicating its potential to reduce virulence. Proteomic and <i>in vitro</i> induced resistance analyses indicate that Benz inhibits protein synthesis and turnover. Additionally, Benz induces membrane depolarization and increases membrane permeability, likely by targeting the membrane phospholipid phosphatidylethanolamine (PE). In the mouse wound infection model, Benz promotes wound healing and significantly reduces bacterial load. These findings suggest that Benz is a promising candidate for developing new antibacterial therapies against Gram-positive bacterial infections.