@article{e27ab1e6d43b41009a1d90c77fa3e4d3,
title = "An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris",
abstract = "Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.",
author = "Iyer, {Kali R.} and Kaddy Camara and Martin Daniel-Ivad and Richard Trilles and Pimentel-Elardo, {Sheila M.} and Fossen, {Jen L.} and Karen Marchillo and Zhongle Liu and Shakti Singh and Mu{\~n}oz, {Jos{\'e} F.} and Kim, {Sang Hu} and Porco, {John A.} and Cuomo, {Christina A.} and Williams, {Noelle S.} and Ibrahim, {Ashraf S.} and Edwards, {John E.} and Andes, {David R.} and Nodwell, {Justin R.} and Brown, {Lauren E.} and Luke Whitesell and Nicole Robbins and Cowen, {Leah E.}",
note = "Funding Information: We thank Dr. Anuradha Chowdhary for the C. auris strain VPCI 673/P/12, the CDC and Dr. Philipp Dufresne for the C. auris strain B12037, Dr. T.C. White for the C. albicans clinical isolates, and Dr. Lawrence Myers for providing that plasmid constructs used for strain construction in C. albicans. We also wish to thank Dr. Norman Lee (Boston University) for assistance with high-resolution mass spectrometry analysis. Finally, we thank members of the Cowen lab, past and present, for their constant support and valuable discussions. K.R.I. is supported by an Ontario Graduate Scholarship. L.E.C. is supported by the Canadian Institutes of Health Research Foundation Grant (FDN-154288); L.E.C. is a Canada Research Chair (Tier 1) in Microbial Genomics & Infectious Disease and co-Director of the CIFAR Fungal Kingdom: Threats & Opportunities program. Work at the BU-CMD is supported by U01 TR002625, R24 GM111615 and R35 GM118173. J.F.M. and C.A.C. are supported by NIAID award U19AI110818 to the Broad Institute; C.A.C. is a CIFAR fellow in the Fungal Kingdom Program. J.R.N. is supported by the Canadian Institutes of Health Research Open Operating Grant (MOP-133636). A.S.I. and J.E. are supported by a NIAID award R01AI141202. D.R.A is supported by an NIH Grant R01AI073289. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
doi = "10.1038/s41467-020-20183-3",
language = "English (US)",
volume = "11",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}