Exposure to Tebuconazole Drives Cross-Resistance to Clinical Triazoles in Aspergillus fumigatus

TL;DR

Exposure to tebuconazole, an agricultural triazole, leads to cross-resistance in Aspergillus fumigatus against clinical triazoles.

Contribution

Demonstrates that agricultural triazoles can induce stable multidrug resistance in Aspergillus fumigatus.

Findings

Resistant strains showed MIC increases up to 128× for itraconazole after tebuconazole exposure.

Proteomics identified 14 resistance-related proteins, including those in ergosterol and efflux pathways.

Resistance phenotypes were stable even in the absence of tebuconazole.

Abstract

Multiazole-resistant Aspergillus fumigatus threatens antifungal therapy.
This study investigated the impact
of prolonged exposure to the agricultural triazole tebuconazole (TEB)
on the susceptibility of A. fumigatus to clinical triazoles and its resistance mechanisms. After 28 days,
resistant strains emerged with substantial increases in minimum inhibitory
concentrations (MICs): up to 128× for itraconazole, 64×
for posaconazole, and 16× for voriconazole. In the absence of
TEB, resistance was maintained and associated with maintenance of
CYP51A activity, with stable ergosterol levels and efflux pump activity.
Among the 193 upregulated proteins identified in proteomics, 14 were
related to resistance, 5 to the ergosterol biosynthesis pathway, 7
to the efflux pump activity, and 2 to the heat shock response pathway.
These results demonstrate that agricultural triazoles can induce stable
and multidrug-resistant phenotypes, emphasizing the need for surveillance
of antifungal resistance in environmental and clinical settings.

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