Dissection of the Activity of Agricultural Fungicides against Clinical Aspergillus Isolates with and without Environmentally and Medically Induced Azole Resistance

Abstract

Azole resistance is an emerging problem in patients with aspergillosis. The role of fungicides for resistance development and occurrence is not fully elucidated. EUCAST reference MICs of 17 fungicides (11 azoles and 6 others), five azole fungicide metabolites and four medical triazoles were examined against two reference and 28 clinical isolates of A. fumigatus, A. flavus and A. terreus with (n = 12) and without (n = 16) resistance mutations. Eight/11 azole fungicides were active against wild-type A. fumigatus, A. flavus and A. terreus, including four (metconazole, prothioconazole-desthio, prochloraz and imazalil) with low MIC50 (≤2 mg/L) against all three species and epoxiconazole, propiconazole, tebuconazole and difenoconazole also against wild-type A. terreus. Mefentrifluconazole, azole metabolites and non-azole fungicides MICs were >16 mg/L against A. fumigatus although partial growth inhibition was found with mefentrifluconazole. Moreover, mefentrifluconazole and axozystrobin were active against wild-type A. terreus. Increased MICs (≥3 dilutions) were found for TR34/L98H, TR34(3)/L98H, TR46/Y121F/T289A and G432S compared to wild-type A. fumigatus for epoxiconazole, propiconazole, tebuconazole, difenoconazole, prochloraz, imazalil and metconazole (except G432S), and for prothioconazole-desthio against TR46/Y121F/T289A, specifically. Increased MICs were found in A. fumigatus harbouring G54R, M220K and M220R alterations for five, one and one azole fungicides, respectively, compared to MICs against wild-type A. fumigatus. Similarly, increased MICs wer found for A. terreus with G51A, M217I and Y491H alterations for five, six and two azole fungicides, respectively. Azole fungicides showed activity against wild-type A. fumigatus, A. terreus and A. flavus, but not against all mutant isolates, suggesting the environmental route of azole resistance may have a role for all three species.

Azole Use in Agriculture, Horticulture, and Wood Preservation – Is It Indispensable?

“…The net yield responses from standard fungicide treatments in Northern-European countries are negative in 1 to 2 seasons out of 10 ( Jalli et al., 2020 ), which indicates that no fungicide treatments should have been carried out in those years. This highlights the necessity of introducing prediction schemes to support farmers’ decision-making ( Jørgensen et al., 2020b ).…”

“…An extensive Chinese survey has linked the prevalence of resistant A. fumigatus in agricultural fields to the applications of azole fungicides ( Cao et al., 2021 ). Specific studies showed variations in the different azoles’ selection potential as a result of variable sensitivity and affinity to the target gene in A. fumigatus ( Snelders et al., 2012 ; Jørgensen et al., 2021b ). Although a lot of research has been dedicated to this topic in recent years, the role of azole fungicides for resistance development and occurrence in A. fumigatus has not yet been fully elucidated ( Gisi, 2014 ; Barber et al., 2020 ; Fraaije et al., 2020 ).…”

Aspergillus-Human Interactions: From the Environment to Clinical Significance

“…Azole fungicides, i.e., bromuconazole, difenoconazole, epoxiconazole, enilconazole, metconazole, prochloraz, propiconazole, prothioconazole-desthio, and tebuconazole, play an important role in the development of environment-derived azole-resistant Aspergillus isolates leading to cross resistance to medical azoles [169,172,173].…”

Selection and Amplification of Fungicide Resistance in Aspergillus fumigatus in Relation to DMI Fungicide Use in Agronomic Settings: Hotspots versus Coldspots

“…Many triazoles and imidazoles are active against A. fumigatus [20,21], hence the introduction of medical triazole therapies to combat CPA and IA in the late 1980s [6,10]. Triazoles are currently the first-line choice of medical treatment for patients suffering from these conditions.…”

“…A number of DMI fungicides used in the outside environment are intrinsically active against A. fumigatus [20,21,56,57]. Cross-resistance in ARAf isolates to these DMIs and the different triazoles used in medicine is common, but not always the case, depending on the genetic configuration of the ARAf genotype [20,52,57].…”