Cationic Ru^II Cyclopentadienyl Complexes with Antifungal Activity against Several Candida Species

Fungal infections, including those caused by antifungal-resistant Candida, are a very challenging health problem worldwide. Whereas different ruthenium complexes were previously studied for their anti-Candida potential, Ru-cyclopentadienyl complexes were overlooked. Here, we report an antifungal activity assessment of three Ru-cyclopentadienyl complexes with some insights into their potential mode of action. Among these complexes, only the cationic species [Ru-ACN]⁺ and [Ru-ATZ]⁺ displayed a significant antifungal activity against different Candida strains, notably against the ones that did not respond to one of the most currently used antifungal drugs fluconazole (FCZ). However, no apparent activity was observed for the neutral species, Ru-Cl, thus indicating the important role of the cationic backbone of these complexes in their biological activity. We suggest that reactive oxygen species (ROS) generation might be involved in the mechanism of action of these complexes as, unlike neutral Ru-Cl, [Ru-ACN]⁺ and [Ru-ATZ]⁺ could generate intracellular concentration-dependent ROS. We also observed a correlation between the ruthenium cellular uptake, ROS generation and fungal growth inhibitory activity of the compounds. Furthermore, docking simulations showed that the CYP51 enzyme can form more energetically favorable complexes with [Ru-ATZ]⁺ than fluconazole (FCZ); this suggests that CYP51 inhibition could also be considered as a potential mode of action.