An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris
Open Access
- 22 December 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-17
- https://doi.org/10.1038/s41467-020-20183-3
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01AI141202)
- U.S. Department of Health & Human Services | National Institutes of Health (R01AI073289, GM111615, GM118173)
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
This publication has 71 references indexed in Scilit:
- An Integrated Approach for Identification and Target Validation of Antifungal Compounds Active against Erg11pAntimicrobial Agents and Chemotherapy, 2012
- Discovery of new antimalarial chemotypes through chemical methodology and library developmentProceedings of the National Academy of Sciences of the United States of America, 2011
- Identification and Characterization of Four Azole-Resistant erg3 Mutants of Candida albicansAntimicrobial Agents and Chemotherapy, 2010
- Drug-Induced Regulation of Target ExpressionPLoS Computational Biology, 2010
- A Phenotypic Profile of the Candida albicans Regulatory NetworkPLoS Genetics, 2009
- Identification of Nile red as a fluorescent substrate of the Candida albicans ATP-binding cassette transporters Cdr1p and Cdr2p and the major facilitator superfamily transporter Mdr1pAnalytical Biochemistry, 2009
- Functional Analysis of cis - and trans -Acting Elements of the Candida albicans CDR2 Promoter with a Novel Promoter Reporter SystemEukaryotic Cell, 2009
- Stereoselective Synthesis of Spirocyclic Oxindoles via Prins CyclizationsOrganic Letters, 2009
- Relative Contributions of the Candida albicans ABC Transporters Cdr1p and Cdr2p to Clinical Azole ResistanceAntimicrobial Agents and Chemotherapy, 2009
- Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungalsCurrent Genetics, 1995