Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation Academic Article uri icon

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abstract

  • AbstractFungal 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.

authors

  • Revie, Nicole M
  • Iyer, Kali R
  • Maxson, Michelle E
  • Zhang, Jiabao
  • Yan, Su
  • Fernandes, Caroline M
  • Meyer, Kirsten J
  • Chen, Xuefei
  • Skulska, Iwona
  • Fogal, Meea
  • Sanchez, Hiram
  • Hossain, Saif
  • Li, Sheena
  • Yashiroda, Yoko
  • Hirano, Hiroyuki
  • Yoshida, Minoru
  • Osada, Hiroyuki
  • Boone, Charles
  • Shapiro, Rebecca S
  • Andes, David R
  • Wright, Gerard
  • Nodwell, Justin R
  • Del Poeta, Maurizio
  • Burke, Martin D
  • Whitesell, Luke
  • Robbins, Nicole
  • Cowen, Leah E

publication date

  • June 25, 2022