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The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus

Takanori Furukawa1,2, Norman van Rhijn1,2, Marcin Fraczek1

  • 1Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.

Nature Communications
|January 24, 2020
PubMed

Insights

Antifungal resistance in Aspergillus fumigatus is a major threat. Researchers identified key regulators and found that losing the negative cofactor 2 complex confers broad resistance without impacting fungal pathogenicity.

Area of Science:

  • Medical Mycology
  • Molecular Biology
  • Antimicrobial Resistance

Background:

  • Antifungal resistance, especially to azoles, is a growing global health concern with low survival rates for infected individuals.
  • The molecular mechanisms underlying azole resistance in Aspergillus fumigatus are not fully understood.
  • Clinically relevant resistance may arise from transcriptional changes that enhance drug resistance without compromising pathogenicity.

Purpose of the Study:

  • To identify transcriptional regulators involved in azole resistance in Aspergillus fumigatus.
  • To investigate the role of transcriptional rewiring in conferring antifungal drug resistance.
  • To explore novel therapeutic targets for combating resistant fungal infections.

Main Methods:

  • Genome-wide annotation of transcriptional regulators in Aspergillus fumigatus.
  • Construction and screening of a library of 484 transcription factor null mutants.
  • Assessment of susceptibility to itraconazole, amphotericin B, and terbinafine.

Main Results:

  • Twelve transcriptional regulators were identified as having a role in itraconazole susceptibility.
  • Loss of the negative cofactor 2 complex resulted in resistance to azoles, amphotericin B, and terbinafine.
  • This broad resistance phenotype was observed without a significant reduction in fungal pathogenicity.

Conclusions:

  • Transcriptional rewiring is a significant mechanism for developing azole resistance in Aspergillus fumigatus.
  • The negative cofactor 2 complex is a critical regulator of antifungal drug susceptibility.
  • Targeting this complex may offer a strategy to overcome multidrug resistance in fungal pathogens.

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