Oligonuclear polypyridylruthenium(II) complexes: selectivity between bacteria and eukaryotic cells
Date
2016
Authors
Gorle, A.
Li, X.
Primrose, S.
Li, F.
Feterl, M.
Kinobe, R.
Heimann, K.
Warner, J.
Richard Keene, F.
Grant Collins, J.
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Journal article
Citation
Journal of Antimicrobial Chemotherapy, 2016; 71(6):1547-1555
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Anil K. Gorle, Xin Li, Sebastian Primrose, Fangfei Li, Marshall Feterl, Robert T. Kinobe, Kirsten Heimann, Jeffrey M. Warner, F. Richard Keene, and J. Grant Collins
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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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© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com