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Genetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates
Jochem B Buil1,2, Jos Houbraken3, Monique H Reijers2,4
1Department of Medical Microbiology, Radboud University Medical Center, 6525 GANijmegen, The Netherlands.
Abstract:
Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus. One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).
Insights
Azole antifungal resistance in Aspergillus flavus emerges through genetic mutations during treatment for pulmonary aspergillosis. Characterizing resistant strains reveals key mutations in Cyp51A and multidrug transporters.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Genomics
Background:
- Aspergillus flavus causes pulmonary aspergillosis, treated with azole antifungals.
- Prolonged azole exposure can lead to drug-resistant fungal strains.
- Understanding resistance mechanisms is crucial for effective treatment.
Purpose of the Study:
- To characterize the genetic basis of azole resistance development in Aspergillus flavus.
- To investigate mutations associated with itraconazole and voriconazole resistance.
- To analyze the genetic diversity and adaptation of A. flavus during infection.
Main Methods:
- Isolation and characterization of 11 isogenic A. flavus strains from a patient.
- Short tandem repeat (STR) analysis for genetic relatedness.
- Whole-genome sequencing (WGS) to identify mutations.
- Antifungal susceptibility testing.
Main Results:
- All isolates were genetically related, originating from a single infection.
- Azole resistance developed within three months of treatment.
- Resistant strains frequently harbored a Y119F mutation in the Cyp51A gene.
- One resistant strain showed a V99A mutation in a multidrug transporter (AFLA 083950).
Conclusions:
- Azole resistance in A. flavus can rapidly emerge during patient treatment.
- Mutations in Cyp51A and multidrug transporters are key mechanisms of resistance.
- Genetic adaptation and (epi)genetic changes contribute to phenotypic diversity and resistance.
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