Targeting Arginine Metabolism via ArcR: Blestriarene B Suppresses Staphylococcus aureus Biofilm Formation and Cellular ATP Production

Blestriarene B (BB), a biphenanthrene compound isolated from the medicinal plant Bletilla striata, possesses antibacterial properties against Staphylococcus aureus; however, its molecular target and underlying mechanisms remain unclear. Arginine metabolism plays a pivotal role in antibiotic susceptibility and biofilm development, making this pathway an attractive therapeutic target. Here, we demonstrate that blestriarene B exerts potent antibacterial activity against S. aureus both in vitro and in vivo. Data-independent acquisition (DIA) proteomics analysis suggests that the antibacterial mechanism of blestriarene B involves an interaction with the HTH-type transcriptional regulator ArcR, which is a key regulator of arginine catabolism. Comparative analyses between wild-type and arcR-deficient S. aureus strains confirmed that ArcR is the molecular target of blestriarene B. Further mechanistic studies revealed that blestriarene B inhibits biofilm formation, impairs cellular ATP production, and ultimately induces bacterial death by binding to ArcR. Collectively, these findings identify blestriarene B as a promising antibacterial drug and validate ArcR as a novel target for anti-S. aureus therapeutics.