Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland

Riat, Arnaud; Plojoux, Jérôme; Gindro, Katia; Schrenzel, Jacques; Sanglard, Dominique

doi:10.1128/aac.02088-17

Cited by 52 publications

(49 citation statements)

References 26 publications

(40 reference statements)

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“…Prevalence of ARAf in the UK was found to be lower than that of other European countries and Colombia (16,18,(25)(26)(27)(28)(29) but higher than most Asian countries (24,(30)(31)(32)(33), with the exception of India (29,34). Our findings are also in close agreement with a recent UK-based environmental prevalence study in Wales, where ARAf was detected in 4.5% (30/671) of soil samples, with resistance predominantly found in urban city locations (14).…”

Section: Discussionsupporting

confidence: 91%

Elevated Prevalence of Azole-Resistant Aspergillus fumigatus in Urban versus Rural Environments in the United Kingdom

Sewell

Zhang

Brackin

et al. 2019

Antimicrob Agents Chemother

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Azole resistance in the opportunistic pathogen Aspergillus fumigatus is increasing, dominated primarily by the following two environmentally associated resistance alleles: TR34/L98H and TR46/Y121F/T289A. By sampling soils across the South of England, we assess the prevalence of azole-resistant A. fumigatus (ARAf) in samples collected in both urban and rural locations. We characterize the susceptibility profiles of the resistant isolates to three medical azoles, identify the underlying genetic basis of resistance, and investigate their genetic relationships. ARAf was detected in 6.7% of the soil samples, with a higher prevalence in urban (13.8%) than rural (1.1%) locations. Twenty isolates were confirmed to exhibit clinical breakpoints for resistance to at least one of three medical azoles, with 18 isolates exhibiting resistance to itraconazole, 6 to voriconazole, and 2 showing elevated minimum inhibitory concentrations to posaconazole. Thirteen of the resistant isolates harbored the TR34/L98H resistance allele, and six isolates carried the TR46/Y121F/T289A allele. The 20 azole-resistant isolates were spread across five csp1 genetic subtypes, t01, t02, t04B, t09, and t18 with t02 being the predominant subtype. Our study demonstrates that ARAf can be easily isolated in the South of England, especially in urban city centers, which appear to play an important role in the epidemiology of environmentally linked drug-resistant A. fumigatus.

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Section: Discussionsupporting

confidence: 91%

Elevated Prevalence of Azole-Resistant Aspergillus fumigatus in Urban versus Rural Environments in the United Kingdom

Sewell

Zhang

Brackin

et al. 2019

Antimicrob Agents Chemother

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“…DMI resistance observed in A . fumigatus isolates of environmental and clinical origin in other studies [ 6 , 30 – 32 , 39 , 46 – 48 ] might be associated to much higher azole concentrations in the substrate (and subsequently higher selection pressure) or to certain geographic locations.…”

Section: Discussionmentioning

confidence: 94%

Molecular characterization and sensitivity to demethylation inhibitor fungicides of Aspergillus fumigatus from orange-based compost

et al. 2018

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Aspergillus fumigatus, the causal agent of human aspergilloses, is known to be non-pathogenic in plants. It is present as saprophyte in different types of organic matter and develops rapidly during the high-temperature phase of the composting process. Aspergilloses are treated with demethylation inhibitor (DMI) fungicides and resistant isolates have been recently reported. The present study aims to estimate the abundance, genetic diversity and DMI sensitivity of A. fumigatus during the composting process of orange fruits. Composting of orange fruits resulted in a 100-fold increase in A. fumigatus frequency already after 1 week, demonstrating that the degradation of orange fruits favoured the growth of A. fumigatus in compost. Most of A. fumigatus isolates belonged to mating type 2, including those initially isolated from the orange peel, whereas mating type 1 evolved towards the end of the composting process. None of the A. fumigatus isolates expressed simultaneously both mating types. The 52 investigated isolates exhibited moderate SSR polymorphisms by formation of one major (47 isolates) and one minor cluster (5 isolates). The latter included mating type 1 isolates from the last sampling and the DMI-resistant reference strains. Only few isolates showed cyp51A polymorphisms but were sensitive to DMIs as all the other isolates. None of the A. fumigatus isolates owned any of the mutations associated with DMI resistance. This study documents a high reproduction rate of A. fumigatus during the composting process of orange fruits, requesting specific safety precautions in compost handling. Furthermore, azole residue concentrations in orange-based compost were not sufficient to select A. fumigatus resistant genotypes.

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“…The cyp51A gene is not mutated in the Belgian strains (except CYP-15-91 in which cyp51A was not sequenced), suggesting different mechanisms of azole resistance. In contrast, strains 1799392 and 20089320 isolated from Switzerland have TR 34 tandem repeats at the cyp51 promoter region and L98H amino acid replacement at the Cyp51A (Riat et al, 2018). Initially, the antifungal effect of gallium was tested in two media, GMM and RPMI.…”

Section: Galliummentioning

confidence: 99%

Potential of Gallium as an Antifungal Agent

Bastos¹,

Rossato²,

Valero³

et al. 2019

Front. Cell. Infect. Microbiol.

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There are only few drugs available to treat fungal infections, and the lack of new antifungals, along with the emergence of drug-resistant strains, results in millions of deaths/year. An unconventional approach to fight microbial infection is to exploit nutritional vulnerabilities of microorganism metabolism. The metal gallium can disrupt iron metabolism in bacteria and cancer cells, but it has not been tested against fungal pathogens such as Aspergillus and Candida. Here, we investigate in vitro activity of gallium nitrate III [Ga(NO 3) 3 ] against these human pathogens, to reveal the gallium mechanism of action and understand the interaction between gallium and clinical antifungal drugs. Ga(NO 3) 3 presented a fungistatic effect against azole-sensitive and-resistant A. fumigatus strains (MIC 50/90 = 32.0 mg/L) and also had a synergistic effect with caspofungin, but not with azoles and amphotericin B. Its antifungal activity seems to be reliant on iron-limiting conditions, as the presence of iron increases its MIC value and because we observed a synergistic interaction between gallium and iron chelators against A. fumigatus. We also show that an A. fumigatus mutant (hapX) unable to grow in the absence of iron is more susceptible to gallium, reinforcing that gallium could act by disrupting iron homeostasis. Furthermore, we demonstrate that gallium has a fungistatic effect against different species of Candida ranging from 16.0 to 256.0 mg/L, including multidrug-resistant Candida auris, C. haemulonii, C. duobushaemulonii, and C. glabrata. Our findings indicate that gallium can inhibit fungal pathogens in vitro under iron-limiting conditions, showing that Ga(NO 3) 3 could be a potential therapy not only against bacteria but also as an antifungal drug.

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Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland

Cited by 52 publications

References 26 publications

Elevated Prevalence of Azole-Resistant Aspergillus fumigatus in Urban versus Rural Environments in the United Kingdom

Elevated Prevalence of Azole-Resistant Aspergillus fumigatus in Urban versus Rural Environments in the United Kingdom

Molecular characterization and sensitivity to demethylation inhibitor fungicides of Aspergillus fumigatus from orange-based compost

Potential of Gallium as an Antifungal Agent

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