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

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.F.; Le Pape, P.; Pagniez, F.; Moretto, M.; Weil, T.; Lustigman, S.; Cariou, K.; Mitreva, M.; Sakanari, J.; Gasser, G. (2023). Discovery of new broad-spectrum anti-infectives for eukaryotic pathogens using bioorganometallic chemistry. JOURNAL OF MEDICINAL CHEMISTRY, 66 (23): 15867-15882. doi: 10.1021/acs.jmedchem.3c01333 handle: https://hdl.handle.net/10449/83136

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

Moretto, Marco;Weil, Tobias
;
2023-01-01

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
Antimicrobial agents
Fungi
Genetics
Infectious diseases
Reaction products
Settore BIO/10 - BIOCHIMICA
2023
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.F.; Le Pape, P.; Pagniez, F.; Moretto, M.; Weil, T.; Lustigman, S.; Cariou, K.; Mitreva, M.; Sakanari, J.; Gasser, G. (2023). Discovery of new broad-spectrum anti-infectives for eukaryotic pathogens using bioorganometallic chemistry. JOURNAL OF MEDICINAL CHEMISTRY, 66 (23): 15867-15882. doi: 10.1021/acs.jmedchem.3c01333 handle: https://hdl.handle.net/10449/83136
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