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

Yan Lin, Hyeim Jung, Christina A. Bulman, James Ng, Robin Vinck, Cillian O’Beirne, Shuai Zhong, Matthew S. Moser, Nancy Tricoche, Ricardo Peguero, Robert W. Li, Joseph F. Urban, Patrice Le Pape, Fabrice Pagniez, Marco Moretto, Tobias Weil, Sara Lustigman, Kevin Cariou, Makedonka Mitreva, Judy A. SakanariGilles Gasser

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)15867-15882
Number of pages16
JournalJournal of Medicinal Chemistry
Volume66
Issue number23
DOIs
StatePublished - Dec 14 2023

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