In vitro susceptibility and cellular uptake for a new class of antimicrobial agents: dinuclear ruthenium(II) complexes

• Published in: Journal of antimicrobial chemotherapy Vol. 67; no. 11; pp. 2686 - 2695
• Main Authors: FANGFEI LI, FETERL, Marshall, MULYANA, Yanyan, WARNER, Jeffrey M, GRANT COLLINS, J, RICHARD KEENE, F
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2012; Oxford Publishing Limited (England)
• Subjects: Anti-Infective Agents - metabolism; Anti-Infective Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial agents; Bacteria; Biological and medical sciences; Cells; Escherichia coli; Escherichia coli - drug effects; Flow Cytometry; Fluorescence; Medical sciences; Microbial Sensitivity Tests; Microbial Viability - drug effects; Microscopy, Confocal; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Ruthenium - metabolism; Ruthenium - pharmacology; Staphylococcus aureus; Staphylococcus aureus - drug effects; MBCs; Drug susceptibility test; time-kill curves; Curve; Metal complex; MICs; In vitro; Antimicrobial agent; Uptake; Minimum inhibitory concentration; cellular accumulation; bactericidal metal complexes; Ruthenium complex
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dks291

To determine the in vitro susceptibility and cellular uptake for a series of dinuclear ruthenium(II) complexes [{Ru(phen)(2)}(2){μ-bb(n)}](4+) (Rubb(n)), and the mononuclear complexes [Ru(Me(4)phen)(3)](2+) and [Ru(phen)(2)(bb(7))](2+) against Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli and Pseudomonas aeruginosa. The in vitro susceptibility was determined by MIC and MBC assays, and time-kill curve experiments, while the cellular uptake was evaluated by monitoring the fluorescence of the complexes remaining in the supernatant of the cultures after incubation for various periods of time, flow cytometry and confocal microscopy. Rubb(12) and Rubb(16) are highly active, with MIC and MBC values of 1-2 mg/L (0.5-1 μM) for the two Gram-positive strains and 2-4 mg/L for E. coli and 16-32 mg/L for P. aeruginosa. Rubb(16) showed equal or better activity (on a molar basis) to gentamicin and ampicillin for all strains apart from P. aeruginosa. The relative MBC to MIC values indicated that Rubb(12) and Rubb(16) are bactericidal, and from the time-kill curve experiments, the ruthenium complexes can kill the bacteria within 2-6 h. The cellular uptake studies demonstrated that the observed antimicrobial activity is correlated with the level of uptake of the ruthenium complexes. Confocal microscopy confirmed the cellular uptake of Rubb(16), and tentatively suggested that the ruthenium complex is localized in the bacteria. The inert dinuclear ruthenium(II) complexes Rubb(12) and Rubb(16) have potential as new antimicrobial agents. The structure of the dinuclear ruthenium complexes can be readily further modified in order to increase their selectivity for bacteria over human cells.