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

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 and Leah E. Cowen ()
Additional contact information
Kali R. Iyer: University of Toronto
Kaddy Camara: Boston University
Martin Daniel-Ivad: University of Toronto
Richard Trilles: Boston University
Sheila M. Pimentel-Elardo: University of Toronto
Jen L. Fossen: University of Wisconsin School of Medicine and Public Health
Karen Marchillo: University of Wisconsin School of Medicine and Public Health
Zhongle Liu: University of Toronto
Shakti Singh: Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center
José F. Muñoz: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
Sang Hu Kim: University of Toronto
John A. Porco: Boston University
Christina A. Cuomo: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
Noelle S. Williams: University of Texas Southwestern Medical School
Ashraf S. Ibrahim: Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center
John E. Edwards: Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center
David R. Andes: University of Wisconsin School of Medicine and Public Health
Justin R. Nodwell: University of Toronto
Lauren E. Brown: Boston University
Luke Whitesell: University of Toronto
Nicole Robbins: University of Toronto
Leah E. Cowen: University of Toronto

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-20183-3

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