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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.

journal_name

Nat Commun

journal_title

Nature communications

authors

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 Jr,Cuomo CA,Williams NS,Ibrahim AS,Edwards JE Jr,Andes DR,Nodwell JR,Brown LE,Whitesell L,Ro

doi

10.1038/s41467-020-20183-3

subject

Has Abstract

pub_date

2020-12-22 00:00:00

pages

6429

issue

1

issn

2041-1723

pii

10.1038/s41467-020-20183-3

journal_volume

11

pub_type

杂志文章

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