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Multiresistance to Nonazole Fungicides in Aspergillus fumigatus TR34/L98H Azole-Resistant Isolates
I Gonzalez-Jimenez1, R Garcia-Rubio1, S Monzon2
1Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain.
Abstract:
Drug resistance is a worldwide problem affecting all pathogens. The human fungal pathogen Aspergillus fumigatus coexists in the environment with other fungi targeted by crop protection compounds, being unintentionally exposed to the selective pressure of multiple antifungal classes and leading to the selection of resistant strains. A. fumigatus azole-resistant isolates are emerging in both clinical and environmental settings. Since their approval, azole drugs have dominated clinical treatment for aspergillosis infections and the agriculture fungicide market. However, other antifungal classes are used for crop protection, including benzimidazoles (methyl benzimidazole carbamates [MBCs]), strobilurins (quinolone oxidation inhibitors [QoIs]), and succinate dehydrogenase inhibitors (SDHIs). Mutations responsible for resistance to these fungicides have been widely researched in plant pathogens, but resistance has not been explored in A. fumigatus. In this work, the genetic basis underlying resistance to MBCs, QoIs, and SDHIs was studied in azole-susceptible and -resistant A. fumigatus strains. E198A/Q and F200Y mutations in β-tubulin conferred resistance to MBCs, G143A and F129L substitutions in cytochrome b conferred resistance to QoIs, and H270R/Y mutations in SdhB conferred resistance to SDHIs. Characterization of susceptibility to azoles showed a correlation between strains resistant to these fungicides and the ones with tandem-repeat (TR)-based azole resistance mechanisms. Whole-genome sequencing analysis showed a genetic relationship among fungicide multiresistant strains, which grouped into subclusters that included only strains carrying the TR-based azole resistance mechanisms, indicating a common ancestor/evolution pattern and confirming the environmental origin of this type of azole-resistant A. fumigatus.
Insights
Drug resistance in Aspergillus fumigatus is a growing concern. This study identifies specific genetic mutations conferring resistance to common agricultural fungicides, linking them to azole resistance and suggesting an environmental origin for multi-resistant strains.
Area of Science:
- Mycology
- Antimicrobial Resistance
- Genetics
Background:
- Drug resistance is a significant global health challenge affecting various pathogens.
- The human fungal pathogen Aspergillus fumigatus is increasingly exhibiting azole resistance, impacting clinical treatments and environmental settings.
- Agricultural fungicides, including benzimidazoles (MBCs), strobilurins (QoIs), and SDHIs, exert selective pressure on environmental fungal populations.
Purpose of the Study:
- To investigate the genetic basis of resistance to MBCs, QoIs, and SDHIs in Aspergillus fumigatus.
- To explore the relationship between resistance to these agricultural fungicides and existing azole resistance mechanisms in A. fumigatus.
- To understand the evolutionary patterns and origins of multi-resistant A. fumigatus strains.
Main Methods:
- Studied azole-susceptible and azole-resistant A. fumigatus strains.
- Identified specific mutations in genes encoding β-tubulin, cytochrome b, and SdhB.
- Performed whole-genome sequencing to analyze genetic relationships among resistant strains.
Main Results:
- Specific mutations (E198A/Q, F200Y in β-tubulin) conferred MBC resistance.
- Substitutions (G143A, F129L in cytochrome b) led to QoI resistance.
- Mutations (H270R/Y in SdhB) resulted in SDHI resistance.
- Azole-resistant strains frequently possessed tandem-repeat (TR)-based azole resistance mechanisms.
- Whole-genome sequencing revealed genetic relatedness among fungicide multi-resistant strains, indicating common ancestry and environmental origin.
Conclusions:
- Identified key genetic mutations responsible for resistance to MBC, QoI, and SDHI fungicides in A. fumigatus.
- Demonstrated a correlation between resistance to agricultural fungicides and TR-based azole resistance mechanisms.
- Confirmed the environmental origin and common evolutionary pathway of multi-resistant A. fumigatus strains.
