Abstract / Summary
The increasing prevalence of antifungal resistance in Candida albicans poses significant challenges in managing candidiasis. Silymarin, a flavonolignan mixture derived from milk thistle ( Silybum marianum ), has shown promising antimicrobial properties in prior research. Here, we evaluated the in vitro antifungal activity of free silymarin and its nanoencapsulated form against ten C. albicans isolates, including nine fluconazole-resistant clinical isolates and one reference strain. Nanocapsules were prepared and characterized using scanning electron microscopy (SEM), dynamic light scattering (DLS), and zeta potential measurements, yielding particles with mean diameters of 119.75 nm (SEM) and 157.5 nm (DLS), a polydispersity index (PDI) of 0.407 and a highly negative zeta potential of − 77.9 mV. Susceptibility testing followed CLSI guidelines, revealing that nanoencapsulation improved efficacy: geometric mean minimum inhibitory concentrations (MICs) decreased from 7578.6 µg/mL (free silymarin) to 4061.3 µg/mL (nanosilymarin), while minimum fungicidal concentrations (MFCs) dropped from 15,157.2 to 7578.6 µg/mL. At sub-MIC levels, nanosilymarin reduced cellular ergosterol content to an extent similar to that observed with itraconazole, as measured by high-performance liquid chromatography (HPLC). Molecular docking simulations further indicated robust interactions of silymarin with key targets involved in cell wall integrity and ergosterol biosynthesis (namely Chs2, Erg11, and the transcription factor Upc2) with favorable binding energies of − 10.81, − 10.62, and − 12.84 kcal/mol, respectively. These results suggest that nanoformulation can enhance the antifungal action of silymarin against resistant C. albicans strains, likely through interference with ergosterol production and selective protein targeting.