Mononuclear Polypyridylruthenium(II) Complexes with High Membrane Permeability in Gram‐Negative Bacteria—in particular Pseudomonas aeruginosa

Abstract

Ruthenium(II) complexes containing the tetradentate ligand bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane ("bbn "; n=10 and 12) have been synthesised and their geometric isomers separated. All [Ru(phen)(bbn )](2+) (phen=1,10-phenanthroline) complexes exhibited excellent activity against Gram-positive bacteria, but only the cis-α-[Ru(phen)(bb12 )](2+) species showed good activity against Gram-negative species. In particular, the cis-α-[Ru(phen)(bb12 )](2+) complex was two to four times more active than the cis-β-[Ru(phen)(bb12 )](2+) complex against the Gram-negative strains. The cis-α- and cis-β-[Ru(phen)(bb12 )](2+) complexes readily accumulated in the bacteria but, significantly, showed the highest level of uptake in Pseudomonas aeruginosa. Furthermore, the accumulation of the cis-α- and cis-β-[Ru(phen)(bb12 )](2+) complexes in P. aeruginosa was considerably greater than in Escherichia coli. The uptake of the cis-α-[Ru(phen)(bb12 )](2+) complex into live P. aeruginosa was confirmed by using fluorescence microscopy. The water/octanol partition coefficients (log P) were determined to gain understanding of the relative cellular uptake. The cis-α- and cis-β-[Ru(phen)(bbn )](2+) complexes exhibited relatively strong binding to DNA (Kb ≈10(6) M(-1) ), but no significant difference between the geometric isomers was observed.

Complementary Approaches to Imaging Subcellular Lipid Architectures in Live Bacteria Using Phosphorescent Iridium Complexes and Raman Spectroscopy

“…The emission of the complexes was detected after only one minute of dosing at room temperature (Supporting Information, Video 1). This extremely fast cellular uptake is remarkable, if one considers that previously reported protocols involve incubation times from 30 minutes up to two hours . All the complexes were excited with a 405 nm laser and the emission collected in the 500–700 nm region (see the Supporting Information), consistent with the emission properties of the complexes in aqueous media (Table S1, Supporting Information).…”

“…This extremelyf ast cellular uptake is remarkable, if one considers that previously reported protocols involve incubation times from 30 minutes up to two hours. [14,26,27] All the complexes were excited with a4 05 nm laser and the emission collected in the 500-700nmr egion (see the Supporting Information), consistent with the emission properties of the complexes in aqueous media (Table S1, SupportingI nformation). Acquisition of z-stack images confirmed that the complexes were effectively internalised within the live bacteria and were not interacting with the outer side of the membrane (see the Supporting Information, Video 2).…”

“…Moreover,p roduction of these dyes can be synthetically demanding due to their complex molecular architecture.T his factor might limit mass productionf or widespread use and tunability to obtainaplatform of bacterial markersw ith complementary properties. Intriguingly,c omplexes of Ru II ,R e I ,I r III with luminescent properties have also been investigated in detail as potentiala ntibacterial agents, [23][24][25][26][27] but surprisingly they have not yet been studied as bacteriali maging agents. This growinge ffort to understand the mechanisms of prokaryotic cell biology is driven by the impact it has in clinical and industrial settings.…”

The Antimicrobial Activity of Mononuclear Ruthenium(II) Complexes Containing the dppz Ligand

“…The synthesis of the [Ru(bb 7 )(dppz)] 2+ complex containing the flexible bb 7 ligand is presented in Scheme . To avoid the formation of the dinuclear complex, the [Ru(bb 7 )(dppz)] 2+ was synthesised by direct reaction of bb 7 with the appropriate mole ratio of the precursor complex cis , cis ‐[RuCl 2 (dmso) 2 (dppz)] (dmso=dimethyl sulfoxide) in ethylene glycol as previously reported . The [Ru(bb 7 )(dppz)] 2+ complex was purified by SP Sephadex C‐25 cation‐exchange chromatography.…”

“…The [Ru(bb 7 )(dppz)] 2+ complex was characterised by microanalysis, NMR spectroscopy and high‐resolution electrospray ionisation (ESI) mass spectrometry. The [Ru(bb 7 )(dppz)] 2+ complex displayed a resolvable 1 H NMR spectrum, and all proton chemical shifts were assigned based on the comparison with those of similar compounds . Only one symmetrical set of resonances was observed for both the dppz and bb 7 aromatic protons.…”