Triazole Priming as an Adaptive Response and Gateway to Resistance in Aspergillus fumigatus

Area of Science:

• Mycology
• Antimicrobial Resistance
• Clinical Microbiology

Background:

• Invasive aspergillosis (IA) is a severe opportunistic infection in immunocompromised individuals.
• Increasing resistance of Aspergillus fumigatus to triazoles compromises treatment efficacy.
• Mechanisms of triazole resistance, beyond ergosterol gene mutations, are not fully understood, particularly concerning agricultural azole exposure.

Purpose of the Study:

• To investigate the phenomenon of triazole priming in Aspergillus fumigatus.
• To determine if prior exposure to sublethal triazole concentrations influences subsequent antifungal stress response.
• To explore the characteristics and implications of triazole priming in A. fumigatus.

Main Methods:

• Exposure of A. fumigatus conidia to subinhibitory concentrations of agricultural (tebuconazole, difenoconazole, epoxiconazole) and medical (voriconazole) triazoles.
• Assessment of germination and growth upon subsequent exposure to triazole challenge.
• Evaluation of priming specificity, duration, heritability, and impact on stable resistance development.

Main Results:

• Triazole priming was demonstrated, enhancing germination and growth of A. fumigatus upon reexposure to triazoles.
• Priming was found to be triazole class-specific, isolate-independent, and retained in dormant conidia but not heritable.
• Subinhibitory azole exposure increased the frequency of stable resistance development at inhibitory concentrations.

Conclusions:

• Triazole priming is a novel mechanism in A. fumigatus that enhances survival under triazole stress.
• The widespread use of agricultural azoles may contribute to triazole priming and subsequent antifungal resistance.
• Triazole priming has significant clinical implications for managing invasive aspergillosis, especially in patients with suboptimal azole levels.