Triazine amine compounds synergistically enhance the efficacy against fluconazole-resistant Candida albicans with fluconazole by inhibiting cell wall synthesis.

Invasive fungal infections caused by Candida albicans are associated with high morbidity and mortality, highlighting the urgent need for novel antifungal agents. Compound 2 m in combination with fluconazole exhibited a significant synergistic effect (fractional inhibitory concentration index range: 0.15-0.17) and demonstrated enhanced efficacy against fluconazole-resistant strains. The combination therapy inhibited hyphal growth and biofilm formation, promoted the exposure of cell wall components, and disrupted cell membrane integrity. Transmission electron microscopy confirmed damage to cellular structures. The mechanism of action may be related to the downregulation of cell wall synthesis related genes (WSC1, WSC2, and FKS1) to inhibit C. albicans activity. This combination therapy reduced the renal fungal burden and inflammation in vivo, improved survival, and restored immune function. Additionally, compound 2 m demonstrated low cytotoxicity, suggesting its potential as an antimicrobial enhancer for fluconazole, and augmenting its inhibitory effect against fungal strains through synergistic effects, thereby offering a novel strategic approach for antifungal therapy.