Oligonuclear polypyridylruthenium(II) complexes: Selectivity between bacteria and eukaryotic cells

Objectives: The objectives of this studywere to: (i) determine the in vitro activities of a series of di-, tri- and tetra-nuclear ruthenium complexes (Rubb_n, Rubb_n-tri and Rubb_n-tetra) against a range of Gram-positive and -negative bacteria and compare the antimicrobial activities with the corresponding toxicities against eukaryotic cells; and (ii) compare MIC values with achievable in vivo serum concentrations for the least toxic ruthenium complex. Methods: The in vitro activities were determined by MIC assays and time-kill curve experiments, while the toxicities of the ruthenium complexes were determined using the Alamar blue cytotoxicity assay. A preliminary pharmacokinetic study was undertaken to determine the Rubb₁₂ serum concentration inmice as a function of time after administration. Results: Rubb₁₂, Rubb₁₂-tri and Rubb₁₂-tetra are highly active, with MIC values of 1-2 mg/L (0.5-1.5 μM) for a range of Gram-positive strains, but showed variable activities against a panel of Gram-negative bacteria. Time-kill experiments indicated that Rubb₁₂, Rubb₁₂-tri and Rubb₁₂-tetra are bactericidal and kill bacteria within 3-8 h. The di-, tri- and tetranuclear complexes were ~50 times more toxic to Gram-positive bacteria and 25 times more toxic to Gram-negative strains, classified as susceptible, than to liver and kidney cells. Preliminary pharmacokinetic experiments established that serum concentrations higher than MIC values can be obtained for Rubb₁₂ with an administered dose of 32 mg/kg. Conclusions: The ruthenium complexes, particularly Rubb₁₂, have potential as new antimicrobial agents. The structure of the dinuclear ruthenium complex can be readily furthermodified in order to increase the selectivity for bacteria over eukaryotic cells.