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

Abstract

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.

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

“…In fact, A . fumigatus is commonly found in compost piles, plant material in decomposition, and wastewater from urban areas [ 98 ]. Thus, studies that did not detect resistant strains eventually assume the soil as hotspot of resistance emergence, when it might actually be importing this condition.…”

“…These environments contain several characteristics that may facilitate not only the emergence of azole-resistant strains, but also their maintenance, and spread [ 19 , 20 ]. Such chacharacteristic are beyond the scopus of this review and has been recentely well discussed by Burks and colleagues [ 98 ]. Besides the fact that not all the soil or culture seems to be favorable for the emergence of resistant strains, it appears that are some DMIs more prone to select mutations in A .…”

“…In the environment, azole-resistant isolates harboring the aforementioned genetic modifications have been isolated from several places and materials, including leaves, plant seeds, soil samples, flowerbeds, compost, hospital surroundings, and air samples [ 19 , 20 , 22 , 24 , 26 , 34 , 49 , 93 , 98 ]. In this way, some researchers have been reporting potential hotspot to isolate those mutants (especially TR34/L98H and TR46/Y121F/T289A), including soils from strawberry fields in China [ 22 ]; azole-exposed compost [ 20 ], flower bulb waste, green waste material, and wood chippings in the Netherlands [ 19 ].…”

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

“…A second widespread "environmental" mutant, TR 46 /Y121F/T289A, was first recovered from a Dutch patient in 2009 [9,10,41,42] and later found in a sample from a US patient taken in 2008 [43]. It too has been detected widely in the environment [44], albeit less frequently than TR 34 /L98H [45]. Further TR-associated mutants, such as a TR 53 mutant without substitutions in the cyp51A gene, have also been detected [9,46].…”

The CCAAT‐binding complex mediates azole susceptibility of Aspergillus fumigatus by suppressing SrbA expression and cleavage

“…Investigation of azole‐resistant A . fumigatus suggests that the primary genetic alteration responsible for azole resistance is found within the erg11A locus (Burks et al, 2021 ). Among these azole‐resistant isolates, the substitution of leucine 98 for histidine (L98H) in the erg11A gene along with two copies of a specific 34‐bp tandem repeat (TR34) in the erg11A promoter (TR34/L98H) resulted in the overexpression of erg11A , which was found to be the predominant resistance mechanism (Chowdhary et al, 2017 ; Mellado et al, 2007 ; Snelders et al, 2008 ; Zhang et al, 2019 ).…”