Evolution of cross-resistance to medical triazoles in<i>Aspergillus fumigatus</i>through selection pressure of environmental fungicides

Zhang, Jianhua; Heuvel, Joost van den; Debets, A.J.M.; Verweij, Paul E.; Melchers, Willem J. G.; Zwaan, Bas J.; Schoustra, Sijmen E.

doi:10.1098/rspb.2017.0635

Cited by 58 publications

(55 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These 5 azole fungicides showed similarities with the molecular structure of medical triazoles and cross-resistance. This finding complements other studies, which showed that various azole fungicides can induce cross-resistance to medical triazoles because all of these compounds affect the CYP51A enzyme that is central in the ergosterol biosynthesis pathway (13,14). Patients with triazole-resistant aspergillus disease have a high probability of treatment failure (15).…”

supporting

confidence: 85%

“…In general, low levels of residues were detected, which challenges the concept of high exposure as the main driver for resistance selection or maintenance, as postulated by Gisi (27). We previously compared the resistance dynamics in 2 compost heaps with and without azole exposure (14) and found that, in the presence of the azole, the dominant phenotype of the A. fumigatus populations differed from predominantly wild-type in the absence of azoles to predominantly resistant in the presence of azoles (14). Exposure to low concentrations of azoles might pose a greater risk for resistance selection than exposure to high concentrations because at lower concentrations, a larger population of fungal cells will be available to produce progeny (28).…”

Section: Discussionmentioning

confidence: 99%

“…We used molecular methods for strain identification and determination of the resistance mechanism as described (17)(18)(19)(20). We determined the full coding sequence of the cyp51A gene by PCR amplification and sequencing (14). We used the cyp51A sequence (GenBank accession no.…”

Section: Sampling Of Potential Hotspotsmentioning

confidence: 99%

See 2 more Smart Citations

Environmental Hotspots for Azole Resistance Selection of Aspergillus fumigatus, the Netherlands

Schoustra¹,

Debets²,

Rijs

et al. 2019

Emerg. Infect. Dis.

Self Cite

116

146

View full text Add to dashboard Cite

Azole resistance is a major concern for treatment of infections with Aspergillus fumigatus . Environmental resistance selection is a main route for Aspergillus spp. to acquire azole resistance. We investigated the presence of environmental hotspots for resistance selection in the Netherlands on the basis of the ability of A. fumigatus to grow and reproduce in the presence of azole fungicide residues. We identified 3 hotspots: flower bulb waste, green waste material, and wood chippings. We recovered azole-resistant A. fumigatus from these sites; all fungi contained cyp51A tandem repeat–mediated resistance mechanisms identical to those found in clinical isolates. Tebuconazole, epoxiconazole, and prothioconazole were the most frequently found fungicide residues. Stockpiles of plant waste contained the highest levels of azole-resistant A. fumigatus , and active aerobic composting reduced Aspergillus colony counts. Preventing plant waste stockpiling or creating unfavorable conditions for A. fumigatus to grow in stockpiles might reduce environmental resistance burden.

show abstract

supporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Environmental Hotspots for Azole Resistance Selection of Aspergillus fumigatus, the Netherlands

Schoustra¹,

Debets²,

Rijs

et al. 2019

Emerg. Infect. Dis.

Self Cite

116

146

View full text Add to dashboard Cite

show abstract

“…However, continual exposure to these compounds exerts selective pressures that can facilitate the evolution of azole-resistant A. fumigatus (ARAf). The recent emergence of two ARAf-associated cyp51A alleles, TR 34 /L98H and TR 46 /Y121F/T289A, has raised concern due to their environmental association and increasing prevalence in azole-naive patients (Abdolrasouli et al, 2018;Chowdhary, Kathuria, Xu, & Meis, 2013;Mellado et al, 2007;Sewell, Zhu, et al, 2019;Snelders, Camps, et al, 2012;Stensvold, Jorgensen, & Arendrup, 2012;Van Der Linden et al, 2013;Zhang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

A Low‐Cost Tebuconazole‐Based Screening Test for Azole‐Resistant Aspergillus fumigatus

et al. 2020

View full text Add to dashboard Cite

The global emergence of azole resistance in Aspergillus fumigatus is resulting in health and food security concerns. Rapid diagnostics and environmental surveillance methods are key to understanding the distribution and prevalence of azole resistance. However, such methods are often associated with high costs and are not always applicable to laboratories based in the least‐developed countries. Here, we present and validate a low‐cost screening protocol that can be used to differentiate between azole‐susceptible “wild‐type” and azole‐resistant A. fumigatus isolates. © 2020 The Authors. Basic Protocol 1: Preparation of Tebucheck multi‐well plates Basic Protocol 2: Inoculation of Tebucheck multi‐well plates

show abstract

“…Zhang et al also induced azole resistance in vitro through the pressure of fungicides including TBCZ. The mutations induced in the obtained isolates were found through genome sequencing (20). However, few such studies have been conducted to shed light on responsible genes for azole tolerance and resistance.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel mutations contributing to azole tolerance ofAspergillus fumigatus throughin vitroexposure to tebuconazole

Toyotome

Onishi

Sato

et al. 2020

Preprint

View full text Add to dashboard Cite

Azole resistance of Aspergillus fumigatus is a global problem. The major resistant mechanism is a cyp51A alteration such as mutation(s) in the gene and the acquisition of a tandem repeat in the promoter. Although other azole tolerances and resistant mechanisms such as hmg1 mutation are known, few reports describe studies elucidating non-cyp51A resistance mechanisms. This study explored genes contributing to azole tolerance in A. fumigatus by in vitro mutant selection with tebuconazole, an azole fungicide. After three-round selection, we obtained four isolates with low susceptibility to tebuconazole. These isolates also showed low susceptibility to itraconazole and voriconazole. Comparison of the genome sequences of the obtained isolates and the parental strain revealed a non-synonymous mutation in MfsD (Afu1g11820, R337L mutation) in all isolates. Furthermore, non-synonymous mutations in AgcA (Afu7g05220, E535Stop mutation), UbcD (Afu3g06030, T98K mutation), AbcJ (Afu3g12220, G297E mutation), and RttA (Afu7g04740, A83T mutation), a protein responsible for tebuconazole tolerance, were found in at least one isolate. Clarification by constructing the MfsD R337L mutant suggests that the mutation contributes to azole tolerance. Disruption of the agcA gene and reconstruction of the A83T point mutation in RttA led to decreased susceptibility to azoles. The reversion of T98K mutation to wild type in UbcD led to the level of azole susceptibility comparable to the parental strain. These results suggest that these mutations contribute to lowered susceptibility to medical azoles and to agricultural azole fungicides.

show abstract

Evolution of cross-resistance to medical triazoles inAspergillus fumigatusthrough selection pressure of environmental fungicides

Cited by 58 publications

References 51 publications

Environmental Hotspots for Azole Resistance Selection of Aspergillus fumigatus, the Netherlands

Environmental Hotspots for Azole Resistance Selection of Aspergillus fumigatus, the Netherlands

A Low‐Cost Tebuconazole‐Based Screening Test for Azole‐Resistant Aspergillus fumigatus

Identification of novel mutations contributing to azole tolerance ofAspergillus fumigatus throughin vitroexposure to tebuconazole

Contact Info

Product

Resources

About