Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis

Kaizhou Yan, Mathew Stanley, Bartosz Kowalski, Olawale Raimi, Andrew Ferenbach, Pingzhen Wei, Wenxia Fang, Daan van Aalten (Lead / Corresponding author)

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Abstract

Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells and is a potential target for antifungal treatments. Glucan is synthesized from the donor uridine diphosphate glucose, with the conversion of glucose-6-phosphate to glucose-1-phosphate by the enzyme phosphoglucomutase (PGM) representing a key step in its biosynthesis. Here, we explore the possibility of selectively targeting A. fumigatus PGM (AfPGM) as an antifungal treatment strategy. Using a promoter replacement strategy, we constructed a conditional pgm mutant and revealed that pgm is required for A. fumigatus growth and cell wall integrity. In addition, using a fragment screen, we identified the thiol-reactive compound isothiazolone fragment of PGM as targeting a cysteine residue not conserved in the human ortholog. Furthermore, through scaffold exploration, we synthesized a para-aryl derivative (ISFP10) and demonstrated that it inhibits AfPGM with an IC 50 of 2 μM and exhibits 50-fold selectivity over the human enzyme. Taken together, our data provide genetic validation of PGM as a therapeutic target and suggest new avenues for inhibiting AfPGM using covalent inhibitors that could serve as tools for chemical validation.

Original languageEnglish
Article number102003
Number of pages20
JournalJournal of Biological Chemistry
Volume298
Issue number6
Early online dateMay 2022
DOIs
Publication statusPublished - Jun 2022

Keywords

  • Aspergillus fumigatus
  • phosphoglucomutase
  • covalent inhibitor
  • isothiazolone
  • antifungal
  • fragment
  • FBDD

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