Gorle, Anil K., Li, Xin, Primrose, Sebastian, Li, Fangfei, Feterl, Marshall, Kinobe, Robert T., Heimann, Kirsten, Warner, Jeffrey M., Keene, F. Richard, and Collins, J. Grant (2016) Oligonuclear polypyridylruthenium(II) complexes: selectivity between bacteria and eukaryotic cells. Journal of Antimicrobial Chemotherapy, 71. pp. 1547-1555.

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Abstract

Objectives: The objectives of this study were to: (i) determine the in vitro activities of a series of di-, tri- and tetra-nuclear ruthenium complexes (Rubbn, Rubbn-tri and Rubbn-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 in mice 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 tetra-nuclear 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 further modified in order to increase the selectivity for bacteria over eukaryotic cells.

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