Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Nat Commun. 2017 May 18;8:15482. doi: 10.1038/ncomms15482.

Abstract

Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / pharmacology*
  • Azabicyclo Compounds / chemical synthesis
  • Azabicyclo Compounds / pharmacology
  • Azepines / pharmacology
  • Benzodiazepines / pharmacology
  • Binding Sites
  • Candida albicans / drug effects*
  • Candida albicans / growth & development
  • Candida albicans / metabolism
  • Candida albicans / pathogenicity
  • Candidiasis / drug therapy*
  • Candidiasis / microbiology
  • Crystallography, X-Ray
  • Fungal Proteins / antagonists & inhibitors*
  • Fungal Proteins / chemistry
  • Fungal Proteins / genetics
  • Gene Expression
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Targeted Therapy*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • Antifungal Agents
  • Azabicyclo Compounds
  • Azepines
  • Fungal Proteins
  • Pyridines
  • Recombinant Proteins
  • Transcription Factors
  • Triazoles
  • Benzodiazepines
  • molibresib