Cationic Oligo(α-lipoic acid)s for Antifungal Therapy

Fungal infections remain a major health burden due to limited treatment options, biofilm-associated tolerance, and increasing emergence of drug-resistant strains. Antifungal polymers have gained growing interest because their molecular structures can be rationally tuned to optimize antifungal activity. Herein, we prepared a series of side-chain-functionalized oligo(α-lipoic acid)s and identified the primary amine-bearing oligomer OLA-EDA as the lead candidate, based on its favorable balance between antifungal activity and cytocompatibility. Mechanistic assays showed that OLA-EDA induced relatively limited fungal membrane depolarization and permeabilization, but markedly increased intracellular reactive oxygen species (ROS) levels. NAC pretreatment partially rescued fungal viability, supporting the involvement of oxidative stress or redox imbalance in the OLA-EDA-mediated antifungal activity. In addition, OLA-EDA inhibited hyphal development and biofilm formation and downregulated related virulence-associated genes. In murine vulvovaginal candidiasis model, OLA-EDA treatment reduced fungal burden and alleviated local inflammation, indicating its potential for topical antifungal therapy.