An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

Thumbnail
License
© The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Date Issued
2020-12-22
Publisher Version
10.1038/s41467-020-20183-3
Author(s)
Iyer, Kali R.
Camara, Kaddy
Daniel-Ivad, Martin
Trilles, Richard
Pimentel-Elardo, Sheila M.
Fossen, Jen L.
Marchillo, Karen
Liu, Zhongle
Singh, Shakti
Muñoz, José F.
Kim, Sang Hu
Porco, John A.
Cuomo, Christina A.
Williams, Noelle S.
Ibrahim, Ashraf S.
Edwards, John E.
Andes, David R.
Nodwell, Justin R.
Brown, Lauren E.
Whitesell, Luke
Robbins, Nicole
Cowen, Leah E.
Share to FacebookShare to TwitterShare by Email
Export Citation
Metadata
Show full item record
Permanent Link
https://hdl.handle.net/2144/42361
Version
Published version
Citation (published version)
Kali R Iyer, Kaddy Camara, Martin Daniel-Ivad, Richard Trilles, Sheila M Pimentel-Elardo, Jen L Fossen, Karen Marchillo, Zhongle Liu, Shakti Singh, José F Muñoz, Sang Hu Kim, John A Porco, Christina A Cuomo, Noelle S Williams, Ashraf S Ibrahim, John E Edwards, David R Andes, Justin R Nodwell, Lauren E Brown, Luke Whitesell, Nicole Robbins, Leah E Cowen. 2020. "An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.." Nat Commun, Volume 11, Issue 1, pp. 6429 - ?. https://doi.org/10.1038/s41467-020-20183-3
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.
Rights
© The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Collections