Discovery of New Broad-Spectrum Anti-Infectives for Eukaryotic Pathogens Using Bioorganometallic Chemistry

Drug
resistance observed with many anti-infectives clearly
highlights
the need for new broad-spectrum agents to treat especially neglected
tropical diseases (NTDs) caused by eukaryotic parasitic pathogens,
including fungal infections. Herein, we show that the simple modification
of one of the most well-known antifungal drugs, fluconazole, with
organometallic moieties not only improves the activity of the parent
drug but also broadens the scope of application of the new derivatives.
These compounds were highly effective in vivo against pathogenic fungal
infections and potent against parasitic worms such as Brugia, which causes lymphatic filariasis and Trichuris, one of the soil-transmitted helminths that infects millions of
people globally. Notably, the identified molecular targets indicate
a mechanism of action that differs greatly from that of the parental
antifungal drug, 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 (NTDs) targeted for elimination by 2030.