Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation
Nicole M. Revie, Kali R. Iyer, Michelle E. Maxson, Jiabao Zhang, Su Yan, Caroline Mota Fernandes, Kirsten J. Meyer, Xuefei Chen, Iwona Skulska, Meea Fogal, Hiram Sánchez, Saif Hossain, Sheena C. Li, Yoko Yashiroda, Hiroyuki Hirano, Minoru Yoshida, Hiroyuki Osada, Charles Boone, Rebecca S. Shapiro, David R. Andes, Gerard D. Wright, Justin R. Nodwell, Maurizio Del Poeta, Martin D. Burke, Luke Whitesell, Nicole Robbins, Leah E. Cowen
Abstract
Fungal infections cause more than 1.5 million deaths annually. With an increase in immune-deficient susceptible populations and the emergence of antifungal drug resistance, there is an urgent need for novel strategies to combat these life-threatening infections. Here, we use a combinatorial screening approach to identify an imidazopyrazoindole, NPD827, that synergizes with fluconazole against azole-sensitive and -resistant isolates of Candida albicans. NPD827 interacts with sterols, resulting in profound effects on fungal membrane homeostasis and induction of membrane-associated stress responses. The compound impairs virulence in a Caenorhabditis elegans model of candidiasis, blocks C. albicans filamentation in vitro, and prevents biofilm formation in a rat model of catheter infection by C. albicans. Collectively, this work identifies an imidazopyrazoindole scaffold with a non-protein-targeted mode of action that re-sensitizes the leading human fungal pathogen, C. albicans, to azole antifungals.