Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007-2009.
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ABSTRACT:
SUBMITTER: van der Linden JW
PROVIDER: S-EPMC3311118 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6590754 | biostudies-literature
Project description:Aspergillus fumigatus is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target (cyp51A). Recently, cyp51A mutations typical for environmental azole resistance acquisition (for example, TR34/L98H) have been reported. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported on several continents. Here we describe, for the first time, the occurrence of azole-resistant A. fumigatus isolates of environmental origin in Switzerland with cyp51A mutations, and we show that these isolates can also be recovered from a few patients. While the TR34/L98H mutation was dominant, a single azole-resistant isolate exhibited a cyp51A mutation (G54R) that was reported only for clinical isolates. In conclusion, our study demonstrates that azole resistance with an environmental signature is present in environments and patients of Swiss origin and that mutations believed to be unique to clinical settings are now also observed in the environment.
| S-EPMC5913999 | biostudies-literature
Project description:The aims of the study were to investigate the prevalence of azole resistance among Aspergillus fumigatus clinical isolates. A total of 533 clinical isolates that had been collected between 1995 and 2006, from 441 patients, were screened. No resistance was detected in isolates collected between 1995 and 1997. Starting in 1998, the resistance rate was 6.9%; a total of 24 patients (6.25%) harbored a resistant isolate. The TR34/L98H substitution was found in 21 of 30 tested isolates.
| S-EPMC4704201 | biostudies-literature
Project description:Drug resistance poses a serious threat to human health and agricultural production. Azole drugs are the largest group of 14-α 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 work we have performed A. fumigatus susceptibility testing to 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 populations groups based on their azole resistance mechanism and previous WGS analysis, which suggests that the different resistance mechanisms have different origins and are specifically associated to 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 of the CDC 2019 Antimicrobial Resistance Threats Report. 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 forthcoming years.
| S-EPMC8090891 | biostudies-literature
Project description:To investigate azole resistance in clinical Aspergillus isolates, we conducted prospective multicenter international surveillance. A total of 3,788 Aspergillus isolates were screened in 22 centers from 19 countries. Azole-resistant A. fumigatus was more frequently found (3.2% prevalence) than previously acknowledged, causing resistant invasive and noninvasive aspergillosis and severely compromising clinical use of azoles.
| S-EPMC4451897 | biostudies-literature
Project description:The emergence and spread of Aspergillus fumigatus azole resistance has been acknowledged worldwide. The main problem of azole resistance is the limited therapeutic options for patients suffering aspergillosis. Azole resistance mechanisms have been mostly linked to the enzyme Cyp51A, a target of azole drugs, with a wide variety of modifications responsible for the different resistance mechanisms described to date. However, there are increasing reports of A. fumigatus strains showing azole resistance without Cyp51A modifications, and thus, novel resistance mechanisms are being explored. Here, we characterized two isogenic A. fumigatus clinical strains isolated two years apart from the same patient. Both strains were resistant to clinical azoles but showed different azole resistance mechanisms. One strain (CM8940) harbored a previously described G54A mutation in Cyp51A while the other strain (CM9640) had a novel G457S mutation in Cyp51B, the other target of azoles. In addition, this second strain had a F390L mutation in Hmg1. CM9640 showed higher levels of gene expression of cyp51A, cyp51B and hmg1 than the CM8940 strain. The role of the novel mutation found in Cyp51B together with the contribution of a mutation in Hmg1 in azole resistance is discussed.
| S-EPMC7712412 | biostudies-literature
Project description:Aspergillus fumigatus is a fungal species causing diverse diseases in humans. The use of azoles for treatments of A. fumigatus diseases has resulted in azole resistance. Azoles are also widely used in the environment for crop protection, which resulted in azole resistance. Resistance is primarily due to mutations in cyp51A, which encodes the target protein for azoles. Here we addressed the occurrence of azole resistance in soils from a vast part of Switzerland. We aimed to associate the use of azoles in the environment with the occurrence of azole resistance. We targeted sample sites from different agricultural environments as well as sites with no agricultural practice (natural sites and urban sites). Starting from 327 sites, 113 A. fumigatus isolates were recovered (2019-2021), among which 19 were azole-resistant (15 with TR34/L98H and four with TR46/Y121F/T289A resistance mutations in cyp51A). Our results show that azole resistance was not associated with a specific agricultural practice. Azoles could be chemically detected in investigated soils, however, their presence was not associated with the occurrence of azole-resistant isolates. Interestingly, genetic markers of resistance to other fungicides were detected but only in azole-resistant isolates, thus reinforcing the notion that A. fumigatus cross-resistance to fungicides has an environmental origin. In conclusion, this study reveals the spreading of azole resistance in A. fumigatus from the environment in Switzerland. The proximity of agricultural areas to urban centers may facilitate the transmission of resistant strains to at-risk populations. Thus, vigilant surveillance is required to maintain effective treatment options for aspergillosis.
| S-EPMC10653585 | biostudies-literature
Project description: Not available
| S-EPMC3647519 | biostudies-literature
Project description:Aspergillosis associated with azole-resistant Aspergillus fumigatus has a mortality rate that can approach 90% in certain patient populations. The best-understood avenue for azole resistance involves changes in the cyp51A gene that encodes the target of azole drugs, lanosterol ?-14 demethylase. The most common azole resistance allele currently described is a linked change corresponding to a change in the coding sequence of cyp51A and a duplication of a 34-bp region in the promoter leading to a tandem repeat (TR). Our previous studies identified a positively acting transcription factor called AtrR that binds to the promoter of cyp51A as well as that of an important membrane transporter protein gene called abcG1 In this work, we characterize two different mutant alleles of atrR, either an overproducing or an epitope-tagged form, causing constitutive activation of this factor. Using an epitope-tagged allele of atrR for chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), the genomic binding sites for AtrR were determined. Close to 900 genes were found to have an AtrR response element (ATRE) in their promoter regions. Transcriptome evaluation by RNA sequencing (RNA-seq) indicated that both alleles led to elevated transcription of a subset of target genes. An electrophoretic mobility shift assay and DNase I protection mapping localized the ATREs in both the abcG1 and cyp51A promoters. The ATRE in cyp51A was located within the 34-bp repeat element. Virulence in a murine model was compromised when AtrR was either deleted or overproduced, indicating that the proper dosage of this factor is key for pathogenesis.IMPORTANCE Aspergillus fumigatus is the major filamentous fungal pathogen in humans. Infections associated with A. fumigatus are often treated with azole drugs, but resistance to these antifungal agents is increasing. Mortality from aspergillosis associated with azole-resistant fungi is extremely high. Previous work has identified transcriptional control of the azole drug target-encoding gene cyp51A as an important contributor to resistance in A. fumigatus Here, we demonstrate that the transcription factor AtrR binds to a region in the cyp51A promoter that is associated with alleles of this gene conferring clinically important azole resistance. Using high-throughput genomic technologies, we also uncover a large suite of target genes controlled by AtrR. These data indicate that AtrR coordinately regulates many different processes involved in drug resistance, metabolism, and virulence. Our new understanding of AtrR function provides important new insight into the pathogenesis of A. fumigatus.
| S-EPMC6414702 | biostudies-literature
Project description:In Aspergillus fumigatus, the most prevalent resistance to azoles results from mutational modifications of the azole target protein Cyp51A, but there are non-cyp51A mutants resistant to azoles, and the mechanisms underlying the resistance of these strains remain to be explored. Here, we identified a novel cytochrome c oxidase, cox7c (W56*), nonsense mutation in the laboratory and found that it caused reduced colony growth and resistance to multiantifungal agents. Meanwhile, we revealed that cold storage is responsible for increased tolerance of conidia to itraconazole (ITC) stress, which further advances azole-resistant mutations (cryopreservation→ITC tolerance→azole resistance). The deletion or mutation of cox7c results explicitly in resistance to antifungal-targeting enzymes, including triazoles, polyenes, and allylamines, required for ergosterol synthesis, or resistance to fungal ergosterol. A high-performance liquid chromatography (HPLC) assay showed that the cox7c knockout strain decreased intracellular itraconazole concentration. In addition, the lack of Cox7c resulted in the accumulation of intracellular heme B. We validated that an endogenous increase in, or the exogenous addition of, heme B was capable of eliciting azole resistance, which was in good accordance with the phenotypic resistance analysis of cox7c mutants. Furthermore, RNA sequencing verified the elevated transcriptional expression levels of multidrug transport genes. Additionally, lower itraconazole-induced reactive oxygen species generation in mycelia of a cox7c-deletion strain suggested that this reduction may, in part, contribute to drug resistance. These findings increase our understanding of how A. fumigatus's direct responses to azoles promote fungal survival in the environment and address genetic mutations that arise from patients or environments.
| S-EPMC9211413 | biostudies-literature