An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.
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.
|Year of Publication||
2020 12 22
|PubMed Central ID||
MOP-133636 / CIHR / Canada
U19 AI110818 / AI / NIAID NIH HHS / United States
FDN-154288 / CIHR / Canada
R01 AI141202 / AI / NIAID NIH HHS / United States
R01 AI073289 / AI / NIAID NIH HHS / United States
U01 TR002625 / TR / NCATS NIH HHS / United States
R35 GM118173 / GM / NIGMS NIH HHS / United States