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; Leah E. Cowen

doi:10.1038/s41467-022-31308-1

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 journal › Article › peer-review

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.

Original language	English (US)
Article number	3634
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31308-1
State	Published - Dec 2022

ASJC Scopus subject areas

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

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10.1038/s41467-022-31308-1

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Revie, N. M., Iyer, K. R., Maxson, M. E., Zhang, J., Yan, S., Fernandes, C. M., Meyer, K. J., Chen, X., Skulska, I., Fogal, M., Sanchez, H., Hossain, S., Li, S., Yashiroda, Y., Hirano, H., Yoshida, M., Osada, H., Boone, C., Shapiro, R. S., ... Cowen, L. E. (2022). Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation. Nature communications, 13(1), Article 3634. https://doi.org/10.1038/s41467-022-31308-1

Revie, NM, Iyer, KR, Maxson, ME, Zhang, J, Yan, S, Fernandes, CM, Meyer, KJ, Chen, X, Skulska, I, Fogal, M, Sanchez, H, Hossain, S, Li, S, Yashiroda, Y, Hirano, H, Yoshida, M, Osada, H, Boone, C, Shapiro, RS, Andes, DR, Wright, GD, Nodwell, JR, Del Poeta, M, Burke, MD, Whitesell, L, Robbins, N & Cowen, LE 2022, 'Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation', Nature communications, vol. 13, no. 1, 3634. https://doi.org/10.1038/s41467-022-31308-1

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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.",

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

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AU - Fernandes, Caroline M.

AU - Meyer, Kirsten J.

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AU - Hossain, Saif

AU - Li, Sheena

AU - Yashiroda, Yoko

AU - Hirano, Hiroyuki

AU - Yoshida, Minoru

AU - Osada, Hiroyuki

AU - Boone, Charles

AU - Shapiro, Rebecca S.

AU - Andes, David R.

AU - Wright, Gerard D.

AU - Nodwell, Justin R.

AU - Del Poeta, Maurizio

AU - Burke, Martin D.

AU - Whitesell, Luke

AU - Robbins, Nicole

AU - Cowen, Leah E.

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N2 - 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.

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Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation

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