@article{c8428fcc26f94723bbac7ea3b4df2040,
title = "Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation",
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.}",
note = "Funding Information: We thank Merck and Genome Canada for making the C. albicans GRACE mutant collections available. We thank Sergio Grinstein for access to resources and his confocal microscope for completion of the FRAP experiments. We thank Mami Yoshimura and Hiromi Kimura for technical support during our screening efforts. We thank all Cowen lab members for helpful discussions. N.M.R. is supported by the Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarships Doctoral Award (CGS-D). K.J.M. is supported by a CIHR Fellowship (MFE-176478). L.E.C. is supported by CIHR Foundation Grant (FDN-154288), is a Canada Research Chair (Tier 1) in Microbial Genomics & Infectious Disease, and is co-Director of the CIFAR Fungal Kingdom: Threats & Opportunities program. D.R.A. is supported by an NIH Grant R01AI073289. M.D.P. is supported by NIH grants AI136934, AI116420, and AI125770, and by the Merit Review Grant I01BX002924 from the Veterans Affairs Program. M.D.P. is also a recipient of the Research Career Scientist Award (IK6 BX005386). C.B. and Y.Y. are supported by JSPS Grant-in-Aid for Scientific Research on Innovative Areas (17H06411) from the Japan Society for the Promotion of Science (JSPS). C.B. is also supported by CIHR Foundation Grant (FDN-143264) and is a fellow of the CIFAR Fungal Kingdom: Threats & Opportunities program. M.Y. is supported by a JSPS Grant-in-Aid for Scientific Research (S) (JP19H05640). M.D.B., J.Z., and S.Y. are supported by NIH Grant R01 5R01AI135812. Funding Information: We thank Merck and Genome Canada for making the C. albicans GRACE mutant collections available. We thank Sergio Grinstein for access to resources and his confocal microscope for completion of the FRAP experiments. We thank Mami Yoshimura and Hiromi Kimura for technical support during our screening efforts. We thank all Cowen lab members for helpful discussions. N.M.R. is supported by the Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarships Doctoral Award (CGS-D). K.J.M. is supported by a CIHR Fellowship (MFE-176478). L.E.C. is supported by CIHR Foundation Grant (FDN-154288), is a Canada Research Chair (Tier 1) in Microbial Genomics & Infectious Disease, and is co-Director of the CIFAR Fungal Kingdom: Threats & Opportunities program. D.R.A. is supported by an NIH Grant R01AI073289. M.D.P. is supported by NIH grants AI136934, AI116420, and AI125770, and by the Merit Review Grant I01BX002924 from the Veterans Affairs Program. M.D.P. is also a recipient of the Research Career Scientist Award (IK6 BX005386). C.B. and Y.Y. are supported by JSPS Grant-in-Aid for Scientific Research on Innovative Areas (17H06411) from the Japan Society for the Promotion of Science (JSPS). C.B. is also supported by CIHR Foundation Grant (FDN-143264) and is a fellow of the CIFAR Fungal Kingdom: Threats & Opportunities program. M.Y. is supported by a JSPS Grant-in-Aid for Scientific Research (S) (JP19H05640). M.D.B., J.Z., and S.Y. are supported by NIH Grant R01 5R01AI135812. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-31308-1",
language = "English (US)",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}