Sodium lignosulfonate inhibits multiple virulent proteins of human fungal pathogen Candida albicans.

Systemic mycoses, particularly those caused by Candida albicans, represent a serious global health concern due to rising multidrug resistance and limited treatment options. This study explores the antifungal potential of sodium lignosulfonate (LIG), a natural phenolic compound, as a multitarget therapeutic agent against various virulence proteins of C. albicans and other pathogenic Candida species. The objective of this study was to further evaluate its multiple-targeting/polypharmacological potential with plausible mode of action against C. albicans. At first, LIG was subjected to in-silico analysis to acquire preliminary knowledge about its multiple targeting potential. Subsequently, some biochemical analyses were performed to demonstrate its fungicidal activity. In-vitro analysis (plasma membrane permeation, ROS production, chitin depletion study) was performed to further validate its promising multiple-targeting/polypharmacological potential and revealed its mechanism of action. Homology modeling and docking studies revealed that LIG effectively binds to critical C. albicans proteins, including ERG1, ERG11, FKS1, CHS3, CLB2, and CEK1. The docking scores indicated strong interactions, supporting LIG's potential to inhibit multiple virulence factors With ROS production we could confirm the involvement of apoptosis. Time-kill assays confirmed the antifungal effect of LIG against C. albicans, C. glabrata, C. tropicalis, and C. parapsilosis. LIG demonstrated a > 3-log10 reduction in CFU/mL, and in combination with fluconazole, it showed synergistic activity, particularly reducing CFU in C. dubliniensis by 2.5-fold compared to fluconazole alone. The chitin depletion assay has reported a decrease in levels of chitin which indicates another aspect of LIG's mode of action. This study reveals LIG as a potent and persuasive natural antifungal agent that targets multiple proteins of Candida. This revelation might impact the direction of potent antifungal agent development by aiming multiple targets of fungal pathogens simultaneously.