In Vitro and In Vivo Studies on a Mononuclear Ruthenium Complex Reveals It is a Highly Effective, Fast-Acting, Broad-Spectrum Antimicrobial in Physiologically Relevant Conditions.

The crystal structure of a previously reported antimicrobial Ru complex that targets bacterial DNA is presented. Studies utilizing clinical isolates of Gram-negative bacteria that cause catheter-associated urinary tract infection, (CA)UTI, in media that model urine and plasma reveal that good antimicrobial activity is maintained in all conditions tested. Experiments with a series of clinical isolates show that, unlike the majority of previously reported Ru-based antimicrobial leads, the compound retains its potent activity even in MRSA strains.

Clearing an ESKAPE Pathogen in a Model Organism; A Polypyridyl Ruthenium(II) Complex Theranostic that Treats a Resistant Acinetobacter baumannii Infection in Galleria mellonella.

In previous studies we have described the therapeutic action of luminescent dinuclear ruthenium(II) complexes based on the tetrapyridylphenazine, tpphz, bridging ligand on pathogenic strains of Escherichia coli and Enterococcus faecalis. Herein, the antimicrobial activity of the complex against pernicious Gram-negative ESKAPE pathogenic strains of Acinetobacter baumannii (AB12, AB16, AB184 and AB210) and Pseudomonas aeruginosa (PA2017, PA_ 007_ IMP and PA_ 004_ CRCN) are reported. Estimated minimum inhibitory concentrations and minimum bactericidal concentrations for the complexes revealed the complex shows potent activity against all A.

A Ruthenium(II) Polypyridyl Complex Disrupts Actin Cytoskeleton Assembly and Blocks Cytokinesis.

The dinuclear Ru complex [(Ru(phen))(tpphz)] (phen=1,10-phenanthroline, tpphz=tetrapyridophenazine) "RuRuPhen" blocks the transformation of G-actin monomers to F-actin filaments with no disassembly of pre-formed F-actin. Molecular docking studies indicate multiple RuRuPhen molecules bind to the surface of G-actin but not the binding pockets of established actin polymerisation inhibitors. In cells, addition of RuRuPhen causes rapid disruption to actin stress fibre organisation, compromising actomyosin contractility and cell motility; due to this effect RuRuPhen interferes with late-stage cytokinesis.

A Ruthenium(II) Polypyridyl Complex Disrupts Actin Cytoskeleton Assembly and Blocks Cytokinesis.

The dinuclear Ru complex [(Ru(phen) ) (tpphz)] (phen=1,10-phenanthroline, tpphz=tetrapyridophenazine) "RuRuPhen" blocks the transformation of G-actin monomers to F-actin filaments with no disassembly of pre-formed F-actin. Molecular docking studies indicate multiple RuRuPhen molecules bind to the surface of G-actin but not the binding pockets of established actin polymerisation inhibitors. In cells, addition of RuRuPhen causes rapid disruption to actin stress fibre organisation, compromising actomyosin contractility and cell motility; due to this effect RuRuPhen interferes with late-stage cytokinesis.

A Minimal Load-and-Lock Ru Luminescent DNA Probe.

Threading intercalators bind DNA with high affinities. Here, we describe single-molecule studies on a cell-permeant luminescent dinuclear ruthenium(II) complex that has been previously shown to thread only into short, unstable duplex structures. Using optical tweezers and confocal microscopy, we show that this complex threads and locks into force-extended duplex DNA in a two-step mechanism.

Ruthenium based antimicrobial theranostics - using nanoscopy to identify therapeutic targets and resistance mechanisms in .

In previous studies we reported that specific dinuclear Ru complexes are particularly active against pathogenic Gram-negative bacteria and, unusually for this class of compounds, appeared to display lowered activity against Gram-positive bacteria. With the aim of identifying resistance mechanisms specific to Gram-positive bacteria, the uptake and antimicrobial activity of the lead complex against SH1000 and other isolates, including MRSA was investigated. This revealed differential, strain specific, sensitivity to the complex.

A Dinuclear Ruthenium(II) Complex Excited by Near-Infrared Light through Two-Photon Absorption Induces Phototoxicity Deep within Hypoxic Regions of Melanoma Cancer Spheroids.

The dinuclear photo-oxidizing Ru complex [{Ru(TAP)}(tpphz)] (TAP = 1,4,5,8- tetraazaphenanthrene, tpphz = tetrapyrido[3,2-:2',3'-:3″,2''-:2‴,3'''-]phenazine), , is readily taken up by live cells localizing in mitochondria and nuclei. In this study, the two-photon absorption cross section of is quantified and its use as a two-photon absorbing phototherapeutic is reported. It was confirmed that the complex is readily photoexcited using near-infrared, NIR, and light through two-photon absorption, TPA.

Making the Right Link to Theranostics: The Photophysical and Biological Properties of Dinuclear Ru-Re dppz Complexes Depend on Their Tether.

The synthesis of new dinuclear complexes containing linked Ru(dppz) and Re(dppz) moieties is reported. The photophysical and biological properties of the new complex, which incorporates a ,'-bis(4-pyridylmethyl)-1,6-hexanediamine tether ligand, are compared to a previously reported Ru/Re complex linked by a simple dipyridyl alkane ligand. Although both complexes bind to DNA with similar affinities, steady-state and time-resolved photophysical studies reveal that the nature of the linker affects the excited state dynamics of the complexes and their DNA photocleavage properties.

Structural Investigation into the Threading Intercalation of a Chiral Dinuclear Ruthenium(II) Polypyridyl Complex through a B-DNA Oligonucleotide.

Herein we report the separation of the three stereoisomers of the DNA light-switch compound [{Ru(bpy)}(tpphz)] (tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2″-h:2‴,3‴-j]phenazine) by column chromatography and the characterization of each stereoisomer by X-ray crystallography. The interaction of these compounds with a DNA octanucleotide d(GCATATCG).d(CGATATGC) has been studied using NMR techniques.

Exploring the Cytotoxicity, Uptake, Cellular Response, and Proteomics of Mono- and Dinuclear DNA Light-Switch Complexes.

Drug resistance to platinum chemotherapeutics targeting DNA often involves abrogation of apoptosis and has emerged as a significant challenge in modern, non-targeted chemotherapy. Consequently, there is great interest in the anti-cancer properties of metal complexes-particularly those that interact with DNA-and mechanisms of consequent cell death. Herein we compare a parent cytotoxic complex, [Ru(phen)(tpphz)] [phen = 1,10-phenanthroline, tpphz = tetrapyridyl[3,2- a:2',3'- c:3″,2″- h:2‴,3‴- j]phenazine], with a mononuclear analogue with a modified intercalating ligand, [Ru(phen)(taptp)] [taptp = 4,5,9,18-tetraazaphenanthreno[9,10- b] triphenylene], and two structurally related dinuclear, tpphz-bridged, heterometallic complexes, RuRe and RuPt.