Glycolysis-mediated energy metabolism mechanisms: Synergistic antifungal activity of (±)-methylagrimonolide against drug-resistant Candida albicans.

Drug-resistant C. albicans infection is difficult to treat, and many studies have shown that energy metabolism disorder caused by glycolysis pathway can be an important research field of antifungal drugs. In present work, in vitro and in vivo antifungal activities of agrimonolide-based compounds combined with FLC. The results indicated that (±)-methylagrimonolide (1) combined with FLC showed good synergistic inhibition against FLC-resistant ATCC14053-FR with MIC50 of 8 μM and FICI of 0.08. In addition, the combined drugs could also improve the survival status and pathological damage of different organs in immunodeficient mice. Further mechanistic studies showed that the combined drugs could reduce the glycolytic products of C. albicans such as ATP and pyruvate by more than 50 % and promote the death of C. albicans. Therefore, (±)-methylagrimonolide acts as a glycolytic-targeting synergetic agent to significantly enhance the antifungal activity of FLC against resistant C. albicans.