Discovery of Ruthenium(Arene) Metalloantibiotics: Advancing Selective and Potent Therapeutics against Gram-Negative

No new class of antibiotics active against Acinetobacter baumannii─a critical WHO priority pathogen (2024)─has reached clinical use in over 50 years. To address this, we designed, synthesized, and characterized a novel library of ruthenium arene complexes and screened them against various bacterial strains. Antibacterial assays identified Ru5 as a potent lead compound, exhibiting ultralow minimum inhibitory concentrations (MICs) against A. baumannii (MIC = 4 μg/mL) and Staphylococcus aureus (MIC = 0.5 μg/mL), with no resistance emerging after 20 passages. Ru5 also showed strong, selective activity against both planktonic and biofilm-associated bacteria, achieving 78% eradication of A. baumannii and 57% of S. aureus at 20 × MIC. Furthermore, Ru5 effectively disrupted polymicrobial cocultured biofilms. Its therapeutic efficacy was validated in a BALB/c mouse skin abscess model infected with A. baumannii. This new chemical class represents a promising foundation for next-generation broad-spectrum antibiotics targeting invasive infections caused by A. baumannii.