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. Andes, Gerard D. Wright, Justin R. Nodwell, Maurizio Del Poeta, Martin D. Burke, Luke Whitesell, Nicole Robbins and Leah E. Cowen ()
Additional contact information
Nicole M. Revie: University of Toronto
Kali R. Iyer: University of Toronto
Michelle E. Maxson: The Hospital for Sick Children
Jiabao Zhang: University of Illinois at Urbana-Champaign
Su Yan: University of Illinois at Urbana-Champaign
Caroline M. Fernandes: Stony Brook University
Kirsten J. Meyer: University of Toronto
Xuefei Chen: McMaster University
Iwona Skulska: University of Guelph
Meea Fogal: University of Guelph
Hiram Sanchez: University of Wisconsin School of Medicine and Public Health
Saif Hossain: University of Toronto
Sheena Li: Donnelly Centre for Cellular and Biomolecular Research
Yoko Yashiroda: RIKEN Center for Sustainable Resource Science, Wako
Hiroyuki Hirano: RIKEN Center for Sustainable Resource Science, Wako
Minoru Yoshida: RIKEN Center for Sustainable Resource Science, Wako
Hiroyuki Osada: RIKEN Center for Sustainable Resource Science, Wako
Charles Boone: Donnelly Centre for Cellular and Biomolecular Research
Rebecca S. Shapiro: University of Guelph
David R. Andes: University of Wisconsin School of Medicine and Public Health
Gerard D. Wright: McMaster University
Justin R. Nodwell: University of Toronto
Maurizio Del Poeta: Stony Brook University
Martin D. Burke: University of Illinois at Urbana-Champaign
Luke Whitesell: University of Toronto
Nicole Robbins: University of Toronto
Leah E. Cowen: University of Toronto

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31308-1

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DOI: 10.1038/s41467-022-31308-1

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