Discovery of new broad-spectrum anti-infectives for eukaryotic pathogens using bioorganometallic chemistry

Authors: LIN, Y - Paris Sciences Et Lettres University; JUNG, H - Washington University School Of Medicine; BULMAN, C. - University Of California San Francisco (UCSF); NG, J - Paris Sciences Et Lettres University; VINCK, R - Paris Sciences Et Lettres University; O'BEIRNE, C. - Paris Sciences Et Lettres University; MOSER, M. - University Of California San Francisco (UCSF); TRICOCHE, N. - Lindsley F Kimball Research Institute(LFKRI); PEGUERO, R. - Lindsley F Kimball Research Institute(LFKRI); Li, Robert; URBAN, J. - Former ARS Employee; LE PAPE, P. - Universite De Nantes; PAGNIEZ, F. - Universite De Nantes; MORETTO, M. - Fondazione Edmund Mach; WEIL, T. - Fondazione Edmund Mach; LUSTIGMAN, S. - Lindsley F Kimball Research Institute(LFKRI); MITREVA, M. - Washington University School Of Medicine; SAKANARI, J. - University Of California San Francisco (UCSF); GASSERA, G. - Paris Sciences Et Lettres University

Submitted to: Journal of Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/10/2023
Publication Date: 11/27/2023
Citation: Lin, Y., Jung, H., Bulman, C.A., Ng, J., Vinck, R., O'Beirne, C., Moser, M.S., Tricoche, N., Peguero, R., Li, R.W., Urban, J., Le Pape, P., Pagniez, F., Moretto, M., Weil, T., Lustigman, S., Mitreva, M., Sakanari, J.A., Gassera, G. 2023. Discovery of new broad-spectrum anti-infectives for eukaryotic pathogens using bioorganometallic chemistry. Journal of Medicinal Chemistry. 66(23):15867-15882. https://doi.org/10.1021/acs.jmedchem.3c01333.
DOI: https://doi.org/10.1021/acs.jmedchem.3c01333

Interpretive Summary: The rapid spread of antimicrobial resistance has imposed significant threats to human health and food animal production by abolishing the efficaciousness of traditional anthelmintics. The search for novel and yet broad-spectrum antimicrobial compounds is becoming urgent. In this study, we demonstrated that the feasibility of the facile structural modulation of a well-established antifungal drug fluconazole. Our findings show that the chemically modified new compounds derived from fluconazole possess potent antifungal and antiparasitic activities. These results provide a roadmap for developing and optimizing novel classes of affordable antimicrobial drugs for a broad range of pathogen controls.

Technical 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.