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Acetylation-mediated fluconazole inactivation: A novel antifungal resistance mechanism

Ludmila Gouveia-Eufrasio1, Gustavo José Cota de Freitas1, Danielle Letícia da Silva1

  • 1Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|January 25, 2026
PubMed

Insights

Fungi like Cryptococcus can deactivate fluconazole using enzymes, a new antifungal resistance mechanism. This discovery, linked to agrochemicals, offers potential new antifungal therapies.

Area of Science:

  • Mycology
  • Antimicrobial Resistance
  • Biochemistry

Background:

  • Antifungal resistance is a growing global health concern.
  • Enzymatic inactivation of antifungals is a known mechanism in bacteria but not previously described in fungi.
  • Cryptococcus species are major causes of cryptococcosis, a serious fungal infection.

Purpose of the Study:

  • To investigate if fungi, specifically Cryptococcus species, can enzymatically inactivate fluconazole.
  • To identify the enzymes and mechanisms involved in fluconazole inactivation.
  • To explore the clinical relevance and potential therapeutic strategies against this resistance mechanism.

Main Methods:

  • Investigated fluconazole inactivation by Cryptococcus deuterogattii and Cryptococcus neoformans.
  • Analyzed gene expression changes in response to agrochemical exposure.
  • Identified enzymes (GCN5, NAT10) responsible for fluconazole acetylation.
  • Assessed the impact of O-acetyl-fluconazole on the binding affinity to 14-α-demethylase.
  • Tested the efficacy of GCN5 and NAT10 inhibitors in restoring fluconazole activity.
  • Detected O-acetyl-fluconazole in patient cerebrospinal fluid samples.

Main Results:

  • Cryptococcus species enzymatically inactivate fluconazole into O-acetyl-fluconazole.
  • Agrochemicals induce overexpression of GCN5 and NAT10, leading to fluconazole acetylation.
  • O-acetyl-fluconazole cannot bind effectively to 14-α-demethylase, rendering fluconazole inactive.
  • Inhibitors of GCN5 and NAT10 restored fluconazole's antifungal activity.
  • The same resistance mechanism was observed in other fungal species.
  • O-acetyl-fluconazole was detected in the cerebrospinal fluid of patients with cryptococcal meningitis.

Conclusions:

  • A novel mechanism of antifungal resistance through enzymatic inactivation of fluconazole has been discovered in fungi.
  • Environmental factors, such as agrochemicals, can influence clinically relevant antifungal resistance via conserved enzymatic pathways.
  • GCN5 and NAT10 inhibitors show promise as adjuvants to overcome fluconazole resistance in fungal infections.
Keywords:
AcetylationCryptococcus sppFluconazole inactivationResistance mechanism

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