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

<b>Introduction.</b> <i>Aspergillus fumigatus</i> phosphoglucomutase (<i>Af</i>PGM) 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.<b>Hypothesis/Gap Statement.</b> Although <i>Af</i>PGM 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.<b>Aim.</b> This study aimed to further characterize the functional contribution of <i>Af</i>PGM to fungal growth, cell wall-related phenotypes, biofilm formation and enzymatic activity.<b>Methodology.</b> A conditional <i>A. fumigatus PalcA::pgm</i> mutant was used to assess growth, soluble <i>β</i>-glucan levels and biofilm formation. Functional complementation was evaluated by heterologous expression of <i>Afpgm</i> in a <i>Saccharomyces cerevisiae pgm2Δ</i> strain. Enzymatic inhibition was examined using the isothiazolone compound ISFP10.<b>Results.</b> Reduced <i>Af</i>PGM activity was associated with impaired growth, altered cell wall-related phenotypes, decreased soluble <i>β</i>-glucan levels and diminished biofilm biomass. Expression of <i>Afpgm</i> restored growth and sedimentation defects in the yeast <i>pgm2Δ</i> mutant to WT levels, confirming functional conservation. ISFP10 inhibited <i>Af</i>PGM activity and disrupted associated fungal phenotypes.<b>Conclusion.</b> These findings further define the functional role of <i>Af</i>PGM in fungal carbohydrate metabolism and cell wall-associated biology. The selective inhibition of <i>Af</i>PGM relative to human phosphoglucomutase supports its potential as a promising target for the development of novel antifungal therapies.