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

Autor:	Lin Y; Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France., Jung H; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Bulman CA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States., Ng J; Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France., Vinck R; Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France., O'Beirne C; Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France., Zhong S; Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France., Moser MS; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States., Tricoche N; Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, New York 10065, United States., Peguero R; Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, New York 10065, United States., Li RW; United States Department of Agricultural Research Service (USDA-ARS), Animal Parasitic Diseases Laboratory, Beltsville, Maryland 20705, United States., Urban JF Jr; United States Department of Agriculture, Diet, Genomics and Immunology Laboratory, Beltsville, Maryland 20705, United States., Le Pape P; Nantes Université, CHU de Nantes, Cibles et Médicaments des Infections et de l'Immunité, IICiMed, UR 1155, F-44000 Nantes, France., Pagniez F; Nantes Université, CHU de Nantes, Cibles et Médicaments des Infections et de l'Immunité, IICiMed, UR 1155, F-44000 Nantes, France., Moretto M; Fondazione Edmund Mach Via E. Mach 1, Research and Innovation Centre, Via E. Mach 1, 38010 San Michele all'Adige, Italy., Weil T; Fondazione Edmund Mach Via E. Mach 1, Research and Innovation Centre, Via E. Mach 1, 38010 San Michele all'Adige, Italy., Lustigman S; Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, New York 10065, United States., Cariou K; Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France., Mitreva M; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, United States.; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, United States., Sakanari JA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States., Gasser G; Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Dec 14; Vol. 66 (23), pp. 15867-15882. Date of Electronic Publication: 2023 Nov 27.
DOI:	10.1021/acs.jmedchem.3c01333
Abstrakt:	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.
Databáze:	MEDLINE
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