Impairing the interaction between Erg11 and cytochrome P450 reductase Ncp1 enhances azoles’ antifungal activities

Azole effectiveness against candidiasis can be compromised by Candida albicans resistance and tolerance, and unfortunately, few clinically useful compounds can enhance azole antifungal activities. We find that the amino acids V234, F235 and L238 of Erg11 are critical for its interaction with Ncp1, and the Ncp1-Erg11 association is important in azole response. Ellipticine and its analog phiKan 083 block this Erg11-Ncp1 interaction by targeting Ncp1, and boost antifungal effects of fluconazole in vitro and in vivo. A series of steps influencing this process-an initial elevation in reactive oxygen species, leading to protein oxidation and misfolding in the endoplasmic reticulum (ER) that causes ER stress. This stress leads to Ca²⁺ release from the ER, mitochondrial Ca²⁺ accumulation and dysfunction, increased ROS production, and apoptosis of C. albicans cells. Overall, disrupting the Erg11-Ncp1 interaction in C. albicans can serve as a useful approach to enhancing the antifungal properties of azoles.