Guar gum-quercetin bioconjugate as a promising multifunctional biomaterial for combating drug-resistant fungal pathogens.

The global emergence of Candida auris, a multidrug-resistant fungal pathogen associated with high transmissibility and limited therapeutic options, highlights the need for new antifungal strategies. In this study, we report the synthesis, characterization, and biological evaluation of a guar gum-quercetin bioconjugate designed to improve the practical applicability of quercetin through covalent conjugation with a biocompatible polysaccharide scaffold and a cystamine-based disulfide linker. The formation of the GG-Cys-Quer conjugate was supported by FTIR, 1H/13C NMR, CHNS elemental analysis, degree-of-substitution estimation, SEM, and TGA. The conjugate showed potent antifungal activity against five clinical C. auris isolates, with MIC and MFC values ranging from 0.030 to 0.245 µg mL-1 and 0.123 to 0.488 µg mL-1, respectively. Against the resistant isolate MRL6057, GG-Cys-Quer showed an MIC of 0.245 µg mL-1, whereas caspofungin showed an MIC of 4.0 µg mL-1 under the same assay conditions. Mechanistic studies showed increased intracellular ROS accumulation, loss of mitochondrial membrane potential, and apoptosis-associated changes, as confirmed by Annexin V/PI staining, with a concentration-dependent increase in late apoptotic/necrotic cell populations at higher exposure levels. Ultrastructural analysis further revealed membrane deformation, pore formation, and cellular collapse, supporting severe fungal cell damage following treatment. In mammalian L929 fibroblasts, GG-Cys-Quer maintained >85% cell viability at MFC-level exposure, indicating preliminary in vitro cytocompatibility. Overall, these findings demonstrate that GG-Cys-Quer is a structurally characterized guar gum-quercetin conjugate with strong in vitro antifungal activity against C. auris and a mechanism involving oxidative stress, mitochondrial dysfunction, and apoptosis-associated fungal cell death. Further side-by-side studies with free quercetin, linker controls, guar gum controls, and in vivo models are required to define the specific contribution of conjugation and assess translational potential.