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An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.
Iyer, Kali R; Camara, Kaddy; Daniel-Ivad, Martin; Trilles, Richard; Pimentel-Elardo, Sheila M; Fossen, Jen L; Marchillo, Karen; Liu, Zhongle; Singh, Shakti; Muñoz, José F; Kim, Sang Hu; Porco, John A; Cuomo, Christina A; Williams, Noelle S; Ibrahim, Ashraf S; Edwards, John E; Andes, David R; Nodwell, Justin R; Brown, Lauren E; Whitesell, Luke; Robbins, Nicole; Cowen, Leah E.
Affiliation
  • Iyer KR; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • Camara K; Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA.
  • Daniel-Ivad M; Clark+Elbing LLP, Boston, MA, USA.
  • Trilles R; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • Pimentel-Elardo SM; Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA.
  • Fossen JL; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • Marchillo K; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Liu Z; Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA.
  • Singh S; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Muñoz JF; Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA.
  • Kim SH; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • Porco JA; Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, CA, USA.
  • Cuomo CA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Williams NS; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • Ibrahim AS; Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA.
  • Edwards JE; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Andes DR; Department of Biochemistry, University of Texas Southwestern Medical School, Dallas, TX, USA.
  • Nodwell JR; Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, CA, USA.
  • Brown LE; David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
  • Whitesell L; Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, CA, USA.
  • Robbins N; David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
  • Cowen LE; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Nat Commun ; 11(1): 6429, 2020 12 22.
Article in En | MEDLINE | ID: mdl-33353950
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Azoles / Candida / Oxindoles Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2020 Document type: Article Affiliation country: Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Azoles / Candida / Oxindoles Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2020 Document type: Article Affiliation country: Country of publication: