Design and Synthesis of Membrane-Targeting Poly-Ruthenium Complexes Containing Quaternary Ammonium Cations with...

Area of Science:

• Coordination Chemistry
• Antimicrobial Drug Discovery
• Materials Science

Background:

• Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant global health threat.
• Development of new antibiotics with novel mechanisms is crucial to combat rising antimicrobial resistance.

Purpose of the Study:

• To synthesize and evaluate novel amphiphilic ruthenium polypyridyl complexes for antibacterial activity.
• To investigate the mechanism of action and therapeutic potential of promising candidates against MRSA.

Main Methods:

• Synthesis of four ruthenium polypyridyl complexes.
• In vitro antibacterial assays against Staphylococcus aureus and MRSA.
• Hemolytic activity assessment and drug resistance induction studies.
• Mechanism of action studies including membrane interaction, permeability, ROS generation, and transcriptomics.
• In vivo efficacy studies in comparison to vancomycin.

Main Results:

• Complex Ru-4, featuring N-methylimidazole and quaternary ammonium cations, demonstrated potent in vitro activity against S. aureus and MRSA.
• Ru-4 exhibited low hemolytic activity and a reduced tendency to induce drug resistance.
• Mechanism involves bacterial membrane disruption, increased permeability, elevated ROS, and content leakage, impacting membrane-related genes.
• In vivo studies showed Ru-4 outperformed vancomycin in treating MRSA infections.

Conclusions:

• Ruthenium complex Ru-4 is a promising therapeutic candidate for treating MRSA infections.
• Its unique mechanism of action and superior in vivo efficacy warrant further investigation.
• This study highlights the potential of ruthenium complexes in addressing the challenge of antibiotic resistance.