Targeting a critical step in fungal hexosamine biosynthesis

Deborah E. A. Lockhart*, Mathew Stanley, Olawale G. Raimi, David A. Robinson, Dominika Boldovjakova, Daniel R. Squair, Andrew T. Ferenbach, Wenxia Fang, Daan M. F. van Aalten*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment, including host defense responses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. Because 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 Dgna1 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 sub-micromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an
antifungal target in A. fumigatus.
Original languageEnglish
Pages (from-to)8678-8691
Number of pages14
JournalJournal of Biological Chemistry
Volume295
Issue number26
Early online date27 Apr 2020
DOIs
Publication statusPublished - 26 Jun 2020

Keywords

  • fungi
  • Aspergillus fumigatus
  • cell wall
  • glucosamine 6-phosphate N-acetyltransferase (Gna1)
  • resistance
  • fragment
  • protein-protein interaction
  • virulence factor
  • chitin
  • antifungal drug development
  • X-ray crystallography
  • ASPERGILLUS-FUMIGATUS
  • PRACTICE GUIDELINES
  • NIKKOMYCIN-Z
  • STRESS-RESPONSE
  • STRUCTURAL VALIDATION
  • MURINE MODEL
  • CELL-WALL
  • GALLERIA-MELLONELLA LARVAE
  • INHIBITORS
  • INFECTIOUS-DISEASES SOCIETY

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  • Cite this

    Lockhart, D. E. A., Stanley, M., Raimi, O. G., Robinson, D. A., Boldovjakova, D., Squair, D. R., Ferenbach, A. T., Fang, W., & van Aalten, D. M. F. (2020). Targeting a critical step in fungal hexosamine biosynthesis. Journal of Biological Chemistry, 295(26), 8678-8691. https://doi.org/10.1074/jbc.RA120.012985