Breaking Down Barriers: CorA Effectively Targets Staphylococcal Biofilms in Vitro and in Vivo

Biofilm‐associated infections caused by Staphylococcus aureus ( S. aureus ) remain notoriously difficult to treat due to their pronounced tolerance to most antibiotics. Here, we evaluated the antibiofilm efficacy of the natural product antibiotic corallopyronin A (CorA) across a panel of strains, including clinically relevant strains differing in their biofilm‐forming capacities and antibiotic resistance profiles. CorA is an alpha‐pyrone antibiotic produced by Corallococcus coralloides . It targets the switch region of the bacterial DNA‐dependent RNA polymerase, thereby blocking transcription initiation at a site distinct from the rifampicin‐binding pocket, and displays potent activity against staphylococci, including MRSA and rifampicin‐resistant S. aureus . In vitro, CorA eradicated and inhibited biofilm formation, outperforming the biofilm‐active antibiotics dalbavancin and rifampicin both in optical density measurements and in microscopic analyses. Importantly, CorA had activity against rifampicin‐resistant strains in these assays. In a murine foreign body infection model with S. aureus SA113, CorA treatment resulted in a > 4‐ log 10 reduction in bacterial loads on implanted devices and surrounding tissues, comparable with high‐dose rifampicin, and significantly reduced local inflammation. These findings position CorA as a promising candidate for preventing and managing staphylococcal biofilm‐associated infections, warranting further investigation into its clinical potential.