α-Glucosidase-driven metabolism as a potential therapeutic vulnerability in Candida albicans

Candida albicans remains a leading etiological agent of both mucosal and invasive fungal infections. The increasing prevalence of antifungal resistance and limited therapeutic options pose a significant clinical challenge and highlight the need for novel drug targets. The metabolic plasticity of C. albicans is closely linked to its pathogenicity, as the utilization of diverse carbon sources influences cell wall biogenesis, virulence factor development, and immune evasion. The most significant one is the metabolic enzyme α-glucosidase, which connects carbohydrate metabolism to the processing of N-glycans and the maturation of mannoproteins, contributing to cell wall integrity, adhesion, biofilm formation, and host-pathogen interactions. This article critically evaluates α-glucosidase as a potential metabolic and virulence-associated vulnerability in C. albicans. We combine knowledge of glycoside hydrolase family classification, catalytic mechanisms, the functional roles of α-glucosidases across different organisms, and a specific comparative study of fungal versus human enzymes. The phylogenetic and structural superimposition studies reveal a major evolutionary and three-dimensional divergence between fungal GH13 α-glucosidases and human GH31 homologs, despite the preservation of important catalytic sites. These differences create exploitable structural and physicochemical distinctions in the substrate-binding environment, providing a basis for the rational design of selective antifungal inhibitors with minimal off-target activity against human enzymes. Based on our previous research, we reported that the repurposing potential of α-glucosidase inhibitors, particularly acarbose, to demonstrate anti-virulence and antibiofilm activity against C. albicans at concentrations of 90-200 nM, and that these effects were synergistic when combined with existing antifungal agents. This review highlights that in silico modeling, docking studies, and targeted delivery strategies are beneficial tools that drive the development of α-glucosidase-based antifungal therapies. Collectively, this review underscores α-glucosidase-driven metabolism as a potential therapeutic vulnerability in C. albicans, providing a foundation for the rational drug design of metabolism-targeted antifungal strategies to overcome resistance and improve clinical outcomes.