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 M. Fernandes, Kirsten J. Meyer, Xuefei Chen, Iwona Skulska, Meea Fogal, Hiram Sanchez, Saif Hossain, Sheena Li, Yoko Yashiroda, Hiroyuki Hirano, Minoru Yoshida, Hiroyuki Osada, Charles Boone, Rebecca S. Shapiro, David R. AndesGerard D. Wright, Justin R. Nodwell, Maurizio Del Poeta, Martin D. Burke, Luke Whitesell, Nicole Robbins, Leah E. Cowen

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number3634
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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