title: Antimicrobial Properties of Tris(homoleptic) Ruthenium(II) 2-Pyridyl-1,2,3-triazole "Click" Complexes against Pathogenic Bacteria, Including Methicillin-Resistant Staphylococcus aureus (MRSA).
abstract: A series of tris(homoleptic) ruthenium(II) complexes of 2-(1-R-1H-1,2,3-triazol-4-yl)pyridine "click" ligands (R-pytri) with various aliphatic (R = butyl, hexyl, octyl, dodecyl, and hexdecyl) and aromatic (R = phenyl and benzyl) substituents was synthesized in good yields (52%-66%). The [Ru(R-pytri)3]2+(X-)2complexes (where X-= PF6-or Cl-) were characterized by elemental analysis, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS),1H and13C nuclear magnetic resonance (NMR) and infrared (IR) spectroscopies, and the molecular structures of six of the compounds confirmed by X-ray crystallography.1H NMR analysis showed that the as-synthesized materials were a statistical mixture of the mer- and fac-[Ru(R-pytri)3]2+complexes. These diastereomers were separated using column chromatography. The electronic structures of the mer- and fac-[Ru(R-pytri)3]2+complexes were examined using ultraviolet-visible (UV-Vis) spectroscopy and cyclic and differential pulse voltammetry. The family of R-pytri ligands and the corresponding mer- and fac-[Ru(R-pytri)3]2+complexes were tested for antimicrobial activity in vitro against both Staphylococcus aureus and Escherichia coli bacteria. Agar-based disk diffusion assays indicated that two of the [Ru(R-pytri)3](X)2complexes (where X = PF6-and R = hexyl or octyl) displayed good antimicrobial activity against Gram-positive S. aureus and no activity against Gram-negative E. coli at the concentrations tested. The most active [Ru(R-pytri)3]2+complexes ([Ru(hexpytri)3]2+and Ru(octpytri)3]2+) were converted to the water-soluble chloride salts and screened for their activity against a wider range of pathogenic bacteria. As with the preliminary screen, the complexes showed good activity against a variety of Gram-positive strains (minimum inhibitory concentration (MIC) = 1-8 μg/mL) but were less effective against Gram-negative bacteria (MIC = 16-128 μg/mL). Most interestingly, in some cases, the ruthenium(II) "click" complexes proved more active (MIC = 4-8 μg/mL) than the gentamicin control (MIC = 16 μg/mL) against two strains of methicillin-resistant S. aureus (MRSA) (MR 4393 and MR 4549). Transmission electron microscopy (TEM) experiments and propidium iodide assays suggested that the main mode of action for the ruthenium(II) R-pytri complexes was cell wall/cytoplasmic membrane disruption. Cytotoxicity experiments on human dermal keratinocyte and Vero (African green monkey kidney epithelial) cell lines suggested that the complexes were only modestly cytotoxic at concentrations well above the MIC values.
authors.affiliation: Department of Chemistry, University of Otago , PO Box 56, Dunedin, New Zealand.|Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago , PO Box 56, Dunedin, New Zealand.
authors.forename: Sreedhar V
authors.initials: SV
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, University of Otago , PO Box 56, Dunedin, New Zealand.|Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago , PO Box 56, Dunedin, New Zealand.
authors.forename: Synøve Ø
authors.initials: SØ
authors.lastname: Scottwell
authors.affiliation: Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago , PO Box 56, Dunedin, New Zealand.
authors.forename: Emily
authors.initials: E
authors.lastname: Waugh
authors.affiliation: Department of Chemistry, University of Otago , PO Box 56, Dunedin, New Zealand.
authors.forename: C John
authors.initials: CJ
authors.lastname: McAdam
authors.affiliation: Department of Chemistry, University of Otago , PO Box 56, Dunedin, New Zealand.
authors.forename: Lyall R
authors.initials: LR
authors.lastname: Hanton
authors.affiliation: Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago , PO Box 56, Dunedin, New Zealand.
authors.forename: Heather J L
authors.initials: HJ
authors.lastname: Brooks
authors.affiliation: Department of Chemistry, University of Otago , PO Box 56, Dunedin, New Zealand.
authors.forename: James D
authors.initials: JD
authors.lastname: Crowley
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D002522:Chlorocebus aethiops; D057930:Click Chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D055664:Electrochemical Techniques; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D056831:Coordination Complexes; D011725:Pyridines; D014230:Triazoles