Metal-ruthenium complex based on dipyridylamine group as membrane-active antibacterial agent effectively decrease the...

Area of Science:

• Coordination Chemistry
• Antimicrobial Agents
• Drug Resistance

Background:

• Staphylococcus aureus (S. aureus) is a Gram-positive bacterium notorious for developing drug resistance.
• Drug-resistant S. aureus infections result in significant morbidity and mortality.
• Novel therapeutic strategies are crucial to combat the rising threat of antimicrobial resistance.

Purpose of the Study:

• To synthesize and evaluate novel ruthenium complexes for their antibacterial activity against S. aureus.
• To investigate the mechanism of action of the most potent complex.
• To assess the potential of these complexes as antibiotic adjuvants.

Main Methods:

• Synthesis of three ruthenium complexes: [Ru(dpa)2(PSPIP)](PF6)2 (Ru1), [Ru(dpa)2(TSPIP)](PF6)2 (Ru2), and [Ru(dpa)2(TBPIP)](PF6)2 (Ru3).
• In vitro antibacterial assays against S. aureus and hemolytic toxicity tests.
• Fluorescence staining and scanning electron microscopy (SEM) to analyze bacterial cell membrane disruption.
• In vivo studies using Galleria mellonella larvae and mouse skin infection models.
• Evaluation of biofilm inhibition, hemolytic toxin production, and synergistic effects with existing antibiotics.

Main Results:

• Ru1-3 demonstrated excellent in vitro antibacterial activity against S. aureus with low hemolytic toxicity.
• Ru3 effectively disrupted the S. aureus cell membrane and altered its permeability.
• Ru3 showed low toxicity in G. mellonella larvae and efficacy in both larvae and mouse infection models.
• Ru3 inhibited S. aureus biofilm formation and hemolytic toxin production, mitigating resistance development.
• Ru3 exhibited synergistic effects with amikacin, kanamycin, tobramycin, and chloramphenicol.

Conclusions:

• The synthesized ruthenium complexes, particularly Ru3, possess significant antibacterial properties against S. aureus.
• Ru3's mechanism involves bacterial cell membrane disruption, offering a novel approach to combat resistant strains.
• Ru3 shows promise as a safe and effective antibiotic adjuvant, enhancing the efficacy of conventional antibiotics and potentially overcoming resistance.