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

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.