Abstract
BackgroundAzoles play an important role in the management of Aspergillus diseases. Azole resistance is an emerging global problem in Aspergillus fumigatus, and may develop through patient therapy. In addition, an environmental route of resistance development has been suggested through exposure to 14α-demethylase inhibitors (DMIs). The main resistance mechanism associated with this putative fungicide-driven route is a combination of alterations in the Cyp51A-gene (TR34/L98H). We investigated if TR34/L98H could have developed through exposure to DMIs.Methods and FindingsThirty-one compounds that have been authorized for use as fungicides, herbicides, herbicide safeners and plant growth regulators in the Netherlands between 1970 and 2005, were investigated for cross-resistance to medical triazoles. Furthermore, CYP51-protein homology modeling and molecule alignment studies were performed to identify similarity in molecule structure and docking modes. Five triazole DMIs, propiconazole, bromuconazole, tebuconazole, epoxiconazole and difenoconazole, showed very similar molecule structures to the medical triazoles and adopted similar poses while docking the protein. These DMIs also showed the greatest cross-resistance and, importantly, were authorized for use between 1990 and 1996, directly preceding the recovery of the first clinical TR34/L98H isolate in 1998. Through microsatellite genotyping of TR34/L98H isolates we were able to calculate that the first isolate would have arisen in 1997, confirming the results of the abovementioned experiments. Finally, we performed induction experiments to investigate if TR34/L98H could be induced under laboratory conditions. One isolate evolved from two copies of the tandem repeat to three, indicating that fungicide pressure can indeed result in these genomic changes.ConclusionsOur findings support a fungicide-driven route of TR34/L98H development in A. fumigatus. Similar molecule structure characteristics of five triazole DMIs and the three medical triazoles appear the underlying mechanism of cross resistance development. Our findings have major implications for the assessment of health risks associated with the use of triazole DMIs.
Highlights
Aspergillus fumigatus is the most frequent cause of Aspergillus diseases in humans, which include allergic syndromes, aspergilloma and chronic or acute invasive aspergillosis
Our findings support a fungicide-driven route of TR34/L98H development in A. fumigatus
Our findings have major implications for the assessment of health risks associated with the use of triazole demethylase inhibitors (DMIs)
Summary
Aspergillus fumigatus is the most frequent cause of Aspergillus diseases in humans, which include allergic syndromes, aspergilloma and chronic or acute invasive aspergillosis. Antifungal agents of the azole class play a prominent role in the management of Aspergillus diseases. Azole resistance is commonly due to mutations in the cyp51A-gene, encoding the target enzyme of antifungal azoles, and both preclinical evidence and clinical experience suggests that reduced in vitro susceptibility is associated with increased probability of failure to azole therapy [2,3,4]. Azole resistance may develop during azole therapy, which has been primarily reported in patients with aspergilloma or other Aspergillus cavities that received long-term azole therapy [5]. This route of resistance development is characterized by recovery of azole-resistant A. fumigatus isolates exclusively from patients receiving azole therapy and by a high diversity of resistance mechanisms. We investigated if TR34/L98H could have developed through exposure to DMIs
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