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Promising synergistic interactions and mixture optimization of safranal, crocin, and crocetin from Moroccan Crocus sativus L. with enhanced antimicrobial activity

Year: 2026

Type: article

Abstract: This study explores the antimicrobial activity of three principal bioactive constituents of Crocus sativus L.—safranal, crocin, and crocetin—using a simplex-centroid mixture design to evaluate their individual and synergistic effects. Twelve formulations were tested against Staphylococcus aureus , Escherichia coli , Candida albicans , and Geotrichum candidum . Minimum inhibitory concentrations (MICs) were determined via microdilution assays, and the results were fitted using special cubic regression models. The models exhibited strong predictive accuracy (R 2 = 0.97–0.99). Safranal showed the highest individual activity against S. aureus (σ 1 = 169.77, p = 0.0053), while crocin exerted the strongest effect on E. coli (σ 2 = 166.63, p < 0.0001). Significant synergistic interactions were observed between crocin and crocetin for both bacterial strains (σ 23 = −290.34 for S. aureus ; −170.28 for E. coli ). Ternary mixtures displayed superior efficacy compared to single compounds, producing the lowest MIC values across all pathogens. The optimal antibacterial formulation—33.31% safranal, 33.29% crocin, and 33.39% crocetin—yielded MICs of 41.14% (v/v) (predicted) and 39.5% ± 0.75% (v/v) (experimental) against E. coli . Against S. aureus , a blend of 27% safranal, 33% crocin, and 38% crocetin resulted in a predicted MIC of 42.15% (v/v) , confirmed experimentally at 38.13% ± 1.33% (v/v) . For G. candidum , the optimized mixture reached MIC values of 9.13% (v/v) (predicted) and 10.24% ± 2.05% (v/v) (observed). These findings demonstrate that synergistic combinations of saffron-derived metabolites markedly enhance antimicrobial potency. Moreover, mixture design modeling emerges as an effective predictive and optimization strategy for developing reproducible, plant-based antimicrobial formulations targeting antibiotic resistance.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1734075