Membrane-active mechanisms for ruthenium-based antibacterial agents

The emergence of antibiotic resistance has become a serious health concern as the pipeline of new therapeutic agents continues to decline. 

Dinuclear polypyridylruthenium(II) complexes bridged by a flexible methylene linker have been found to have antibacterial potency rivalling that of conventional antibiotics, while also maintaining activity against drug-resistant strains. A collaborative effort involving researchers from the University of Melbourne, the University of Adelaide, James Cook University, the University of New South Wales and IBM Research Australia, which combined solid-state NMR and molecular dynamics simulations, found that selective antibacterial activity of the potent [{Ru(phen)2}2(μ-bb12)]4+ complex (Rubb12), where phen = 1,10-phenanthroline and bb12 = bis[4(4¢-methyl-2,2¢-bipyridyl)]-1,12-dodecane), depends on its insertion into anionic bacterial membranes (Weber D.K., Sani M.-A., Downton M.T., Separovic F., Keene F.R., Collins J.G. J. Am. Chem. Soc. 2016, 138, 15 267–77). 

This contrasts with the highly charged, but biologically inactive, iridium analogue [{Ir(phen)2}2(m-bb12)]6+ (Irbb12), which was not capable of insertion. Incorporation of these biconically shaped complexes in extended conformation induced a significant degree of membrane thinning, which may be either a membrane- disruptive mechanism in itself or perhaps a helpful intermediate in the process of uptake to reach intracellular targets (i.e. nucleic acids).