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Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene

Peiying Chen1, Musang Liu2,3, Qiuqiong Zeng1

  • 1Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.

Frontiers in Microbiology
|February 11, 2020
PubMed

Insights

Azole resistance in Aspergillus fumigatus emerges due to mutations in the Cyp51 enzyme. This study identified new mutations conferring resistance, impacting azole therapy efficacy.

Area of Science:

  • Medical Mycology
  • Antimicrobial Resistance
  • Molecular Biology

Background:

  • The opportunistic fungal pathogen *Aspergillus fumigatus* exhibits widespread azole resistance, primarily driven by mutations in the cytochrome P450 enzyme Cyp51.
  • Azole antifungals are crucial for treating invasive aspergillosis, but rising resistance threatens their clinical utility.

Purpose of the Study:

  • To investigate the emergence of azole resistance in *A. fumigatus* under *in vitro* azole selection pressure.
  • To identify novel mutations in the *cyp51A* gene associated with azole resistance.
  • To evaluate the impact of newly identified mutations on azole therapy efficacy *in vivo* and drug-target interactions.

Main Methods:

  • Induction of azole resistance in *A. fumigatus* isolates through *in vitro* drug exposure.
  • Sequencing of the *cyp51A* gene to identify mutations in resistant isolates.
  • Assessment of azole therapy efficacy using the *Galleria mellonella* infection model.
  • Computational modeling to predict the structural impact of mutations on Cyp51A-azole binding.

Main Results:

  • *In vitro* azole treatment successfully induced azole-resistant *A. fumigatus* isolates.
  • Eighteen independent stable azole-resistant isolates were obtained, revealing previously identified mutations (M220K, M220I, M220R, G54E, G54W) and two novel mutations (N248K/V436A, Y433N).
  • The novel Cyp51A mutations N248K/V436A and Y433N were confirmed to reduce azole therapy efficacy in the *Galleria mellonella* model, with Y433N predicted to decrease drug-target binding affinity.

Conclusions:

  • Drug selection pressure is a significant driver for the emergence of previously unidentified *cyp51A* mutations conferring azole resistance in *A. fumigatus*.
  • The identified novel mutations (N248K/V436A, Y433N) contribute to azole resistance and reduced therapeutic efficacy.
  • Understanding these resistance mechanisms is crucial for developing effective antifungal strategies against *A. fumigatus*.
Keywords:
Aspergillus fumigatusCyp51Aazolesdrug resistancemutations

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