scholarly journals Azole-resistant Aspergillus fumigatus in the environment: Identifying key reservoirs and hotspots of antifungal resistance

2021 ◽  
Vol 17 (7) ◽  
pp. e1009711
Author(s):  
Caroline Burks ◽  
Alexandria Darby ◽  
Luisa Gómez Londoño ◽  
Michelle Momany ◽  
Marin T. Brewer
Keyword(s):  
Aspergillus Fumigatus ◽  
Crop Protection ◽  
Pathogenic Fungi ◽  
Sampling Bias ◽  
Azole Resistance ◽  
Antifungal Stewardship ◽  
Respiratory Illnesses ◽  
Plant Matter ◽  
Ergosterol Synthesis ◽  
Opportunistic Human Pathogen

Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan distribution and exists in the environment as a saprotroph on decaying plant matter. Azoles, which target Cyp51A in the ergosterol synthesis pathway, are the primary class of drugs used to treat aspergillosis. Azoles are also used to combat plant pathogenic fungi. Recently, an increasing number of azole-naive patients have presented with pan-azole–resistant strains of A. fumigatus. The TR34/L98H and TR46/Y121F/T289A alleles in the cyp51A gene are the most common ones conferring pan-azole resistance. There is evidence that these mutations arose in agricultural settings; therefore, numerous studies have been conducted to identify azole resistance in environmental A. fumigatus and to determine where resistance is developing in the environment. Here, we summarize the global occurrence of azole-resistant A. fumigatus in the environment based on available literature. Additionally, we have created an interactive world map showing where resistant isolates have been detected and include information on the specific alleles identified, environmental settings, and azole fungicide use. Azole-resistant A. fumigatus has been found on every continent, except for Antarctica, with the highest number of reports from Europe. Developed environments, specifically hospitals and gardens, were the most common settings where azole-resistant A. fumigatus was detected, followed by soils sampled from agricultural settings. The TR34/L98H resistance allele was the most common in all regions except South America where the TR46/Y121F/T289A allele was the most common. A major consideration in interpreting this survey of the literature is sampling bias; regions and environments that have been extensively sampled are more likely to show greater azole resistance even though resistance could be more prevalent in areas that are under-sampled or not sampled at all. Increased surveillance to pinpoint reservoirs, as well as antifungal stewardship, is needed to preserve this class of antifungals for crop protection and human health.

scholarly journals Multi-resistance to non-azole fungicides in Aspergillus fumigatus TR 34 /L98H azole resistant isolates.

2021 ◽  
Author(s):  
I Gonzalez-Jimenez ◽  
R Garcia-Rubio ◽  
S Monzon ◽  
J Lucio ◽  
I Cuesta ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Plant Pathogens ◽  
Crop Protection ◽  
Resistance Mechanisms ◽  
Azole Resistance ◽  
Sequencing Analysis ◽  
Human Fungal Pathogen ◽  
Evolution Pattern ◽  
Environmental Setting ◽  
Resistant Strains

Drug resistance is a worldwide problem affecting all pathogens. The human fungal pathogen Aspergillus fumigatus coexists in the environment with other fungi targeted by crop protection compounds being unintentionally exposed to the selective pressure of multiple antifungal classes leading to the selection of resistant strains. A. fumigatus azole resistant isolates are emerging in both the clinical and environmental setting. Since their approval, azole drugs have dominated the clinical treatment for aspergillosis infections, and the agriculture fungicide market. However, other antifungal classes are used for crop protection including benzimidazoles (MBC), strobilurins (QoIs) and succinate dehydrogenase inhibitors (SDHIs). Mutations responsible for resistance to these fungicides have been widely researched in plant pathogens, but it has not been explored in A. fumigatus . In this work, the genetic basis underlying resistance to MBCs, QoIs and SDHIs were studied in azole susceptible and resistant A. fumigatus strains. E198A/Q and F200Y mutations in the β-tubulin conferred resistance to MBCs, G143A and F129L substitutions in the Cytochrome b to QoIs and H270R/Y mutations in SdhB to SDHIs. Characterization of the susceptibility to azoles showed a correlation between strains resistant to these fungicides and the ones with TR-based azole resistance mechanisms. Whole genome sequencing analysis showed a genetic relationship among fungicide multi resistant strains, which grouped together into subclusters that only included strains carrying the TR-based azole resistance mechanisms, indicating a common ancestor/evolution pattern and confirming the environmental origin of this type of azole resistant A. fumigatus .

scholarly journals Nonrandom Distribution of Azole Resistance across the Global Population of Aspergillus fumigatus

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Thomas R. Sewell ◽  
Jianing Zhu ◽  
Johanna Rhodes ◽  
Ferry Hagen ◽  
Jacques F. Meis ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Aspergillus Fumigatus ◽  
Pathogenic Fungus ◽  
Crop Protection ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Azole Resistance ◽  
Content Type ◽  
Global Population

ABSTRACT The emergence of azole resistance in the pathogenic fungus Aspergillus fumigatus has continued to increase, with the dominant resistance mechanisms, consisting of a 34-nucleotide tandem repeat (TR34)/L98H and TR46/Y121F/T289A, now showing a structured global distribution. Using hierarchical clustering and multivariate analysis of 4,049 A. fumigatus isolates collected worldwide and genotyped at nine microsatellite loci using analysis of short tandem repeats of A. fumigatus (STRAf), we show that A. fumigatus can be subdivided into two broad clades and that cyp51A alleles TR34/L98H and TR46/Y121F/T289A are unevenly distributed across these two populations. Diversity indices show that azole-resistant isolates are genetically depauperate compared to their wild-type counterparts, compatible with selective sweeps accompanying the selection of beneficial mutations. Strikingly, we found that azole-resistant clones with identical microsatellite profiles were globally distributed and sourced from both clinical and environmental locations, confirming that azole resistance is an international public health concern. Our work provides a framework for the analysis of A. fumigatus isolates based on their microsatellite profile, which we have incorporated into a freely available, user-friendly R Shiny application (AfumID) that provides clinicians and researchers with a method for the fast, automated characterization of A. fumigatus genetic relatedness. Our study highlights the effect that azole drug resistance is having on the genetic diversity of A. fumigatus and emphasizes its global importance upon this medically important pathogenic fungus. IMPORTANCE Azole drug resistance in the human-pathogenic fungus Aspergillus fumigatus continues to emerge, potentially leading to untreatable aspergillosis in immunosuppressed hosts. Two dominant, environmentally associated resistance mechanisms, which are thought to have evolved through selection by the agricultural application of azole fungicides, are now distributed globally. Understanding the effect that azole resistance is having on the genetic diversity and global population of A. fumigatus will help mitigate drug-resistant aspergillosis and maintain the azole class of fungicides for future use in both medicine and crop protection.

scholarly journals Characterization of Aspergillus fumigatus cross-resistance between clinical and DMI azole drugs

2020 ◽  
pp. AEM.02539-20 ◽  
Author(s):  
Rocio Garcia-Rubio ◽  
Irene Gonzalez-Jimenez ◽  
Jose Lucio ◽  
Emilia Mellado
Keyword(s):  
Aspergillus Fumigatus ◽  
Clinical Setting ◽  
Opportunistic Infections ◽  
Treatment Options ◽  
Critical Role ◽  
Crop Protection ◽  
Public Health Problem ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Azole Resistance

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.

scholarly journals A Novel Environmental Azole Resistance Mutation inAspergillus fumigatusand a Possible Role of Sexual Reproduction in Its Emergence

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Jianhua Zhang ◽  
Eveline Snelders ◽  
Bas J. Zwaan ◽  
Sijmen E. Schoustra ◽  
Jacques F. Meis ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Sexual Reproduction ◽  
Crop Protection ◽  
Resistance Mutation ◽  
Azole Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Resistance Selection ◽  
Genotype 2

ABSTRACTThis study investigated the dynamics ofAspergillus fumigatusazole-resistant phenotypes in two compost heaps with contrasting azole exposures: azole free and azole exposed. After heat shock, to which sexual but not asexual spores are highly resistant, the azole-free compost yielded 98% (49/50) wild-type and 2% (1/50) azole-resistant isolates, whereas the azole-containing compost yielded 9% (4/45) wild-type and 91% (41/45) resistant isolates. From the latter compost, 80% (36/45) of the isolates contained the TR46/Y121F/T289A genotype, 2% (1/45) harbored the TR46/Y121F/M172I/T289A/G448S genotype, and 9% (4/45) had a novel pan-triazole-resistant mutation (TR463/Y121F/M172I/T289A/G448S) with a triple 46-bp promoter repeat. Subsequent screening of a representative set of clinicalA. fumigatusisolates showed that the novel TR463mutant was already present in samples from three Dutch medical centers collected since 2012. Furthermore, a second new resistance mutation was found in this set that harbored four TR46repeats. Importantly, in the laboratory, we recovered the TR463mutation from a sexual cross between two TR46isolates from the same azole-containing compost, possibly through unequal crossing over between the double tandem repeats (TRs) during meiosis. This possible role of sexual reproduction in the emergence of the mutation was further implicated by the high level of genetic diversity of STR genotypes in the azole-containing compost. Our study confirms that azole resistance mutations continue to emerge in the environment and indicates compost containing azole residues as a possible hot spot. Better insight into the biology of environmental resistance selection is needed to retain the azole class for use in food production and treatment ofAspergillusdiseases.IMPORTANCEComposting of organic matter containing azole residues might be important for resistance development and subsequent spread of resistance mutations inAspergillus fumigatus. In this article, we show the dominance of azole-resistantA. fumigatusin azole-exposed compost and the discovery of a new resistance mutation with clinical relevance. Furthermore, our study indicates that current fungicide application is not sustainable as new resistance mutations continue to emerge, thereby threatening the use of triazoles in medicine. We provide evidence that the sexual part of the fungal life cycle may play a role in the emergence of resistance mutations because under laboratory conditions, we reconstructed the resistance mutation through sexual crossing of two azole-resistantA. fumigatusisolates derived from the same compost heap. Understanding the mechanisms of resistance selection in the environment is needed to design strategies against the accumulation of resistance mutations in order to retain the azole class for crop protection and treatment ofAspergillusdiseases.

Long Terminal Repeat Retrotransposon Afut4 promotes azole resistance of Aspergillus fumigatus by enhancing the expression of sac1 gene

2021 ◽  
Author(s):  
Mandong Hu ◽  
Zongwei Li ◽  
Dingchen Li ◽  
Fangyan Chen ◽  
Jingya Zhao ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Long Terminal Repeat ◽  
Long Terminal Repeat Retrotransposons ◽  
Terminal Repeat ◽  
Whole Genome Sequence ◽  
Azole Resistance ◽  
Whole Genome ◽  
Expression Of Genes ◽  
Ergosterol Synthesis ◽  
Resistant Strains

Aspergillus fumigatus causes a series of invasive diseases, including the high-mortality invasive aspergillosis, and has been a serious global health threat because of its increased resistance to the first-line clinical triazoles. We analyzed the whole-genome sequence of 15 A. fumigatus strains from China and found that long terminal repeat retrotransposons (LTR-RTs), including Afut1 , Afut2, Afut3, and Afut4 , are most common and have the largest total nucleotide length among all transposable elements in A. fumigatus . Deleting one of the most enriched Afut4 977-sac1 in azole-resistant strains decreased azole resistance and downregulated its nearby gene, sac1 , but it did not significantly affect the expression of genes of the ergosterol synthesis pathway. We then discovered that 5'LTR of Afut4 977-sac1 had promoter activity and enhanced the adjacent sac1 gene expression. We found that sac1 is important to A. fumigatus , and the upregulated sac1 caused the elevated resistance of A. fumigatus to azoles. Finally, we showed that Afut4 977-sac1 has an evolution pattern similar to that of the whole genome of azole-resistant strains due to azoles; phylogenetic analysis on both the whole genome and Afut4 977-sac1 suggests that the insertion of Afut4 977-sac1 might have preceded the emergence of azole-resistant strains. Taking these data together, we found that LTR-RT Afut4 977-sac1 might be involved in the regulation of azole resistance of A. fumigatus by upregulating its nearby sac1 gene.

Genetic Diversity and Azole Resistance Among Natural Aspergillus fumigatus Populations in Yunnan, China

2021 ◽  
Author(s):  
Duanyong Zhou ◽  
Ruirui Wang ◽  
Xiao Li ◽  
Bin Peng ◽  
Guangzhu Yang ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Aspergillus Fumigatus ◽  
Azole Resistance

scholarly journals Non-Thermal Plasma Treatment Influences Shoot Biomass, Flower Production and Nutrition of Gerbera Plants Depending on Substrate Composition and Fertigation Level

Plants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 689
Author(s):  
Samantha Cannazzaro ◽  
Silvia Traversari ◽  
Sonia Cacini ◽  
Sara Di Di Lonardo ◽  
Catello Pane ◽  
...  
Keyword(s):  
Thermal Plasma ◽  
Crop Protection ◽  
Environmental Safety ◽  
Shoot Biomass ◽  
Flower Production ◽  
Plant Matter ◽  
Yield And Quality ◽  
Promising Strategy ◽  
Non Thermal Plasma ◽  
Growing Conditions

Non-thermal plasma (NTP) appears a promising strategy for supporting crop protection, increasing yield and quality, and promoting environmental safety through a decrease in chemical use. However, very few NTP applications on containerized crops are reported under operational growing conditions and in combination with eco-friendly growing media and fertigation management. In this work, NTP technology is applied to the nutrient solution used for the production of gerbera plants grown in peat or green compost, as an alternative substrate to peat, and with standard or low fertilization. NTP treatment promotes fresh leaf and flower biomass production in plants grown in peat and nutrient adsorption in those grown in both substrates, except for Fe, while decreasing dry plant matter. However, it causes a decrease in the leaf and flower biomasses of plants grown in compost, showing a substrate-dependent effect under a low fertilization regime. In general, the limitation in compost was probably caused by the high-substrate alkalinization that commonly interferes with gerbera growth. Under low fertilization, a reduction in the photosynthetic capacity further penalizes plant growth in compost. A lower level of fertilization also decreases gerbera quality, highlighting that Ca, Mg, Mn, and Fe could be reduced with respect to standard fertilization.

scholarly journals Constraints on the evolution of azole resistance in plant pathogenic fungi

2013 ◽  
Vol 62 ◽  
pp. 36-42 ◽  
Author(s):  
H. J. Cools ◽  
N. J. Hawkins ◽  
B. A. Fraaije
Keyword(s):  
Pathogenic Fungi ◽  
Azole Resistance ◽  
Plant Pathogenic Fungi
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