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

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≈106 M−1), but no significant difference between the geometric isomers was observed. New activity: The inert mononuclear ruthenium(II) complex cis‐α‐[Ru(phen)(bb12)]2+ ion (see picture; phen=1,10‐phenanthroline, bb=bis[4(4′‐methyl‐2,2′‐bipyridyl)]‐1,n‐alkane) readily accumulates in Pseudomonas aeruginosa and showed good activity against it. This Gram‐negative bacterium is of particular worldwide concern because it is naturally resistant to many antimicrobial agents due to the low permeability of its outer membrane.