Targeted Antibacterial Strategy Based on Reactive Oxygen Species Generated from Dioxygen Reduction Using an Organoruthenium Complex

Pathogenic microorganisms pose a serious threat to global public health due to their persistent adaptation and growing resistance to antibiotics. Alternative therapeutic strategies are required to address this growing threat. Bactericidal antibiotics that are routinely prescribed to treat infections rely on hydroxyl radical formation for their therapeutic efficacies. We developed a redox approach to target bacteria using organotransition metal complexes to mediate the reduction of cellular O2 to H2O2, as a precursor for hydroxyl radicals via Fenton reaction. We prepared a library of 480 unique organoruthenium Schiff-base complexes using a coordination-driven three-component assembly strategy and identified the lead organoruthenium complex Ru1 capable of selectively invoking oxidative stress in Gram-positive bacteria, in particular methicillin-resistant Staphylococcus aureus, via transfer hydrogenation reaction and/or single electron transfer on O2. This strategy paves the way for a targeted antimicrobial approach leveraging on the redox chemistry of organotransition metal complexes to combat drug resistance.