Aspergillus fumigatus Cross-Resistance between Clinical and Demethylase Inhibitor Azole Drugs

Drug resistance poses a serious threat to human health and agricultural production. Azole drugs are the largest group of 14-alpha sterol demethylation inhibitor fungicides that are used both in agriculture and in clinical practice. As plant-pathogenic molds share their natural environment with fungi that cause opportunistic infections in humans, both are exposed to a strong and persistent pressure of demethylase inhibitor (DMI) fungicides, including imidazole and triazole drugs. As a result, a loss of efficacy has occurred for this drug class in several species. In the clinical setting, Aspergillus fumigatus azole resistance is a growing public health problem, and finding the source of this resistance has gained much attention. It is urgent to determine if there is a direct link between the agricultural use of azole compounds and the different A. fumigatus resistance mechanisms described for clinical triazoles. In this study, we performed A. fumigatus susceptibility testing against clinical triazoles and crop protection DMIs using a collection of azole-susceptible and -resistant strains which harbor most of the described azole resistance mechanisms. Various DMI susceptibility profiles have been found in the different A. fumigatus population groups based on their azole resistance mechanism and previous whole-genome sequencing (WGS) analysis, which suggests that the different resistance mechanisms have different origins and are specifically associated with the local use of a particular DMI. IMPORTANCE Due to the worldwide emergence of A. fumigatus azole resistance, this opportunistic pathogen poses a serious health threat, and therefore, it has been included in the watch list in the CDC publication Antibiotic Resistance Threats in the United States, 2019 (CDC, 2019). Azoles play a critical role in the control and management of fungal diseases, not only in the clinical setting but also in agriculture. Thus, azole resistance leads to a limited therapeutic arsenal which reduces the treatment options for aspergillosis patients, increasing their mortality risk. Evidence is needed to understand whether A. fumigatus azole resistance is emerging from an agricultural source due to the extended use of demethylase inhibitors as fungicides or whether it is coming from somewhere else, such as the clinical setting. If the environmental route is demonstrated, the current use and management of azole antifungal compounds might be forced to change in the coming years.