# Functional and molecular characterization of Aspergillus fumigatus phosphoglucomutase (Pgm): a potential target for antifungal therapy

## TL;DR

This study explores a key enzyme in the fungus Aspergillus fumigatus and shows it could be a target for new antifungal drugs.

## Contribution

The study provides new functional and molecular insights into AfPGM and validates it as a potential antifungal drug target.

## Key findings

- Reduced AfPGM activity impairs fungal growth and cell wall-related traits.
- AfPGM complements a yeast mutant, confirming functional conservation.
- The compound ISFP10 inhibits AfPGM and disrupts fungal phenotypes.

## Abstract

Introduction.
Aspergillus fumigatus phosphoglucomutase (AfPGM) is a central enzyme in fungal carbohydrate metabolism that catalyses the interconversion of glucose-1-phosphate and glucose-6-phosphate, generating precursors such as uridine diphosphate glucose required for the synthesis of key cell wall polysaccharides.

Hypothesis/Gap Statement. Although AfPGM has been implicated in fungal viability and cell wall integrity, further functional and molecular characterization is required to better define its role in cell wall-associated processes and to evaluate its potential as a selective antifungal target.

Aim. This study aimed to further characterize the functional contribution of AfPGM to fungal growth, cell wall-related phenotypes, biofilm formation and enzymatic activity.

Methodology. A conditional A. fumigatus PalcA::pgm mutant was used to assess growth, soluble β-glucan levels and biofilm formation. Functional complementation was evaluated by heterologous expression of Afpgm in a Saccharomyces cerevisiae pgm2Δ strain. Enzymatic inhibition was examined using the isothiazolone compound ISFP10.

Results. Reduced AfPGM activity was associated with impaired growth, altered cell wall-related phenotypes, decreased soluble β-glucan levels and diminished biofilm biomass. Expression of Afpgm restored growth and sedimentation defects in the yeast pgm2Δ mutant to WT levels, confirming functional conservation. ISFP10 inhibited AfPGM activity and disrupted associated fungal phenotypes.

Conclusion. These findings further define the functional role of AfPGM in fungal carbohydrate metabolism and cell wall-associated biology. The selective inhibition of AfPGM relative to human phosphoglucomutase supports its potential as a promising target for the development of novel antifungal therapies.