In vivo active organometallic-containing broad-spectrum anti-infectives for eukaryotic pathogens

Fungal infections are a global problem, especially for immunocompromised patients in hospitals and nursing homes, and the ever-increasing emergence of multidrug-resistant fungal strains poses an imminent threat to many healthcare systems. Azoles are the mainstay of antifungal drugs, and their mode of action involves the binding to the target enzyme, the fungal lanosterol 14a-demethylase. Here, we show that the simple modification of the most widely used antifungal drug, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also extends the scope of application of the new derivatives. These compounds were highly effective in vivo not only against pathogenic fungal infections but also potent across species barriers against parasitic worms that cause elephantiasis and Trichuris, as well as the protozoan parasite responsible for Chagas disease. Remarkably, the identified molecular targets suggest a mechanism of action very different from that of the parental antifungal, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and neglected tropical diseases.