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Azole resistance in Aspergillus flavus and associated fitness cost
Elie Djenontin1,2, Anne Debourgogne3, Bita Mousavi2
1Unité de Parasitologie-Mycologie, Département de Virologie, Bactériologie-Hygiène, Parasitologie-Mycologie, CHU Henri Mondor, AP-HP, Créteil, France.
Background:
The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals - CYP 51 A, B and C - are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood.
Objectives:
This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model.
Methods:
The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole.
Results:
In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent.
Conclusions:
These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus.
Insights
Azole antifungal resistance in Aspergillus flavus is linked to mutations in CYP51A genes, causing reduced virulence and in vitro growth. This study confirms in vivo resistance and informs treatment strategies for azole-resistant fungal infections.
Area of Science:
- Mycology and Infectious Diseases
- Molecular Biology and Genetics
- Antimicrobial Resistance
Background:
- Emerging azole antifungal drug resistance in Aspergillus flavus poses a significant clinical challenge.
- Mutations in CYP51 (cytochrome P450) genes are hypothesized mechanisms for azole resistance, but data are limited.
- The in vitro and in vivo behavior of azole-resistant Aspergillus flavus strains remains poorly understood.
Purpose of the Study:
- To compare CYP51A, B, and C gene sequences between azole-resistant and susceptible Aspergillus flavus strains.
- To investigate potential fitness costs associated with azole resistance in Aspergillus flavus.
- To evaluate the in vivo efficacy of voriconazole and posaconazole against resistant strains using a Galleria mellonella infection model.
Main Methods:
- Comparative sequencing of CYP51A, B, and C genes from seven resistant and four susceptible Aspergillus flavus strains.
- Assessment of fungal growth in RPMI medium and virulence in Galleria mellonella larvae to determine fitness costs.
- In vivo treatment of infected Galleria mellonella larvae with voriconazole and posaconazole to assess antifungal activity.
Main Results:
- Specific nucleotide substitutions (A91T, C708T, A1296T) were identified exclusively in the CYP51A genes of resistant strains.
- Azole-resistant Aspergillus flavus strains exhibited reduced in vitro growth and decreased virulence in Galleria mellonella.
- In vivo resistance to posaconazole was confirmed in a strain displaying high minimum inhibitory concentration (MIC) values.
Conclusions:
- Mutations within CYP51 genes, particularly CYP51A, contribute significantly to azole drug resistance in Aspergillus flavus.
- Further research into the relationship between drug dosage, treatment duration, resistance, and fitness costs is warranted.
- Findings provide a basis for developing treatment recommendations for infections caused by azole-resistant Aspergillus flavus strains.
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