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; Leah E. Cowen

doi:10.1038/s41467-020-20183-3

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 WhitesellNicole Robbins, Leah E. Cowen

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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.

Original language	English (US)
Article number	6429
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20183-3
State	Published - Dec 2020

ASJC Scopus subject areas

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

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Iyer, K. R., Camara, K., Daniel-Ivad, M., Trilles, R., Pimentel-Elardo, S. M., Fossen, J. L., Marchillo, K., Liu, Z., Singh, S., Muñoz, J. F., Kim, S. H., Porco, J. A., Cuomo, C. A., Williams, N. S., Ibrahim, A. S., Edwards, J. E., Andes, D. R., Nodwell, J. R., Brown, L. E., ... Cowen, L. E. (2020). An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris. Nature communications, 11(1), Article 6429. https://doi.org/10.1038/s41467-020-20183-3

Iyer, KR, Camara, K, Daniel-Ivad, M, Trilles, R, Pimentel-Elardo, SM, Fossen, JL, Marchillo, K, Liu, Z, Singh, S, Muñoz, JF, Kim, SH, Porco, JA, Cuomo, CA, Williams, NS, Ibrahim, AS, Edwards, JE, Andes, DR, Nodwell, JR, Brown, LE, Whitesell, L, Robbins, N & Cowen, LE 2020, 'An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris', Nature communications, vol. 11, no. 1, 6429. https://doi.org/10.1038/s41467-020-20183-3

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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.}",

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AU - Iyer, Kali R.

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AU - Daniel-Ivad, Martin

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AU - Pimentel-Elardo, Sheila M.

AU - Fossen, Jen L.

AU - Marchillo, Karen

AU - Liu, Zhongle

AU - Singh, Shakti

AU - Muñoz, José F.

AU - Kim, Sang Hu

AU - Porco, John A.

AU - Cuomo, Christina A.

AU - Williams, Noelle S.

AU - Ibrahim, Ashraf S.

AU - Edwards, John E.

AU - Andes, David R.

AU - Nodwell, Justin R.

AU - Brown, Lauren E.

AU - Whitesell, Luke

AU - Robbins, Nicole

AU - Cowen, Leah E.

PY - 2020/12

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N2 - 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.

AB - 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.

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

Abstract

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