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

• DOI: 10.1038/s41467-020-20183-3
• Publication Date: 2020-12-22T11:03:02Z
• Authors: Kali R. Iyer; Kaddy Camara; Martin Daniel-Ivad; Richard Trilles; Sheila M. Pimente...; 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
• Keywords: Candida auris; Efflux; Azole; Fungal pathogen

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 identify bis-benzodioxolylindolinone (azoffluxin) synergizes with fluconazole against C. auris. Azoffluxin enhances activity through inhibition of efflux pump Cdr1, thus increasing intracellular levels. This conserved across clades, exception clade III. also inhibits in highly azole-resistant strains albicans, another human pathogen, their susceptibility Furthermore, azoffluxin mice infected auris, reducing burden. Our findings suggest pharmacologically targeting Cdr1 combination azoles may be effective strategy control infection caused by isolates