Small-molecule inhibitors block NorA efflux by conformational trapping.

IMP-2380 effectively inhibits the NorA efflux pump in Staphylococcus aureus, restoring antibiotic susceptibility with low-nanomolar potency and structural trapping of the transporter.

• Why it matters: Efflux pumps like NorA contribute significantly to antibiotic resistance, and understanding their inhibition is crucial for developing new therapies. However, limited structural insights and selective inhibitors have hindered progress in this area.
• What they did: Researchers developed IMP-2380 through high-throughput screening and optimization, then used cryo-electron microscopy at 2.52 Å resolution to determine its binding mode and mechanism of action.
• The result: IMP-2380 traps NorA in an 'outward-open' conformation, blocking substrate binding and efflux, which enables potent in vitro potentiation and effective in vivo infection control, providing a valuable tool for combating resistance.