Multi-target antibacterial Ru-based metallodrugs containing phenylsulfonyl indole derivatives: synthesis and their efficacy against Gram-positive and -negative bacteria

The escalating crisis of antimicrobial resistance (AMR) underscores the critical need for the development of novel antibacterial drugs with unique mechanisms of action. Herein, a series of phenylsulfonyl indole-modified Ru-based metallodrugs with multi-target antibacterial mechanisms were prepared and evaluated. Notably, all these complexes showed strong bacteriostatic efficacy against <i>Staphylococcus aureus</i> (<i>S. aureus</i>), and the most active complex, RuS2, showed a lower MIC than that of many common antibiotics. Importantly, RuS2 also showed robust bactericidal efficacy against Gram-negative bacteria (<i>Escherichia coli</i>) in the presence of subinhibitory concentrations of polymyxin B. In addition, complex RuS2 can reduce bacterial pathogenicity by inhibiting hemolysin secretion and biofilm formation. More importantly, RuS2 can curb the production of drug-resistant bacteria and has significant activity against clinically isolated resistant bacteria. Mechanism studies have demonstrated that RuS2 can destroy the bacterial membrane, cause membrane depolarization, and induce the production of reactive oxygen species (ROS). Finally, the <i>G. mellonella</i> wax worms and mouse infection models confirm that RuS2 has low toxicity and significant anti-infective potency <i>in vivo</i>. Taken together, the results presented herein pave a promising way for combating Gram-positive and -negative bacterial infections.