Targeting a critical step in fungal hexosamine biosynthesis
| Autor: | David A. Robinson, Daniel R. Squair, Dominika Boldovjakova, Andrew T. Ferenbach, Daan M. F. van Aalten, Deborah E. A. Lockhart, Mathew Stanley, Olawale G. Raimi, Wenxia Fang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Models Molecular 0301 basic medicine Antifungal Agents Protein Conformation Glucosamine 6-Phosphate N-Acetyltransferase Antifungal drug Virulence Chitin glucosamine 6-phosphate N-acetyltransferase (Gna1) Crystallography X-Ray Microbiology virulence factor fragment Biochemistry Aspergillus fumigatus Small Molecule Libraries protein-protein interaction resistance Cell wall Mice 03 medical and health sciences chemistry.chemical_compound Biosynthesis Cell Wall Glucosamine Catalytic Domain Extracellular Animals Aspergillosis Molecular Targeted Therapy antifungal drug development Molecular Biology X-ray crystallography chemistry.chemical_classification 030102 biochemistry & molecular biology biology Hexosamines Cell Biology biology.organism_classification Biosynthetic Pathways 030104 developmental biology Enzyme chemistry fungi |
| Zdroj: | The Journal of Biological Chemistry 'Journal of Biological Chemistry ', vol: 295, pages: 8678-8691 (2020) |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra120.012985 |
| Popis: | Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective submicromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus. |
| Databáze: | OpenAIRE |
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