Antimicrobial activity of ruthenium-based intercalators

Abstract

Multidrug resistance of bacterial pathogens is a major problem and there is a clear need for the development of new types of antibiotics. Here we investigated the antimicrobial activity of ruthenium(II) based DNA-intercalating complexes. These complexes were found to have no activity in vitro against the Gram-negative bacterium Escherichia coli, but the complexes were clearly active against the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus. In vivo activity has also been demonstrated for one of the compounds using a simple infection model, the nematode Caenorhabditis elegans. Importantly, this also showed that the compound tested was not toxic to the nematodes.

The antimicrobial and antibiofilm activities of copper(II) complexes

“…This has been found to be an important component of the extracellular matrix of biofilms, and for instance DNAse treatment significantly reduces the biomass of biofilms of S. aureus and other bacteria [28]. However, a number of other DNAbinding metallo-complexes that we tested have no or barely any activity on biofilms, including the aforementioned compounds 10 and 11, as well as other compounds such as major groove-binding complexes of iron [22] or ruthenium [23] (data not shown). It is well known that many coordination complexes with copper, but not those with platinum or palladium, are redox active and can mediate DNA cleavage [17].…”

“…In recent years we have investigated the antimicrobial activity of compounds containing iron, ruthenium, copper and palladium [16,[21][22][23][24]. All of these compounds have been reported to bind DNA, either through groove binding or intercalation.…”

“…All of these compounds have been reported to bind DNA, either through groove binding or intercalation. Several compounds showed good antimicrobial activity on both Gramnegative and Gram-positive bacteria, albeit that the latter are generally more sensitive to metal complexes [16,[21][22][23][24]. These complexes have only been tested on planktonic cells, and we therefore sought to investigate the activity of a panel of copper(II) complexes against biofilms, and focussed this specifically on a clinical isolate of meticillin-resistant Staphylococcus aureus (MRSA) that is capable of forming stable 5 biofilms.…”

DNA as a target for antimicrobials

“…This was however not taken forward and these compounds have not been used clinically. Interestingly, the compound was also active in an infection model [21]. In the absence of compound, the soil nematode Caenorhabditis elegans was killed within a few days by MRSA, but the presence of [Ru(2,9-Me 2 phen) 2 (dppz)] 2+ rescued the nematodes from infection.…”

“…A minor groove binder that has been used clinically since the 1940s is the bis-amide pentamidine (21), an important drug in the treatment against a number of protozoal diseases, including those that cause pneumocystis pneumonia, leishmaniasis and African trypanosomiasis (sleeping sickness). From studies with several analogues it was suggested that the isohelical shape of the molecule is important for interaction with the minor groove [35].…”