For this human pathogen, agriculture may be a source of antifungal resistance
Aspergillus fumigatus isolated from clinical settings is resistant to agricultural fungicides.
Infections have long been a deadly problem for hospital patients. Though modern medicine has an impressive array of antimicrobial drugs at its disposal, pathogens continue to evolve resistance, creating ever more dangerous infections as the microbial “arms race” escalates.
Overprescribing of antibiotics is one source of resistance, but there could be another culprit further afield. In a new publication in G3: Genes|Genomes|Genetics, fungal biologists Michelle Momany and Marin Brewer report their finding that some strains of a pathogenic fungus apparently acquired antifungal resistance in an agricultural setting rather than a clinical one. Genetic analysis revealed that strains of the fungus Aspergillus fumigatus that were resistant to antifungals used in people had also developed resistance to fungicides used only on plants.
Fungal infections endanger both plants and people
Momany and Brewer are part of the Fungal Biology Group at the University of Georgia, one of the largest fungal biology research groups in the world. Fungal diseases are a major problem both clinically and in agriculture, but doctors generally use different compounds to treat people than farmers use to treat crops. A class of antifungals known as azoles, however, is used in both people and plants. Many different azoles are currently available, and though they are considered “moderate” in terms of the risk of fungi developing resistance, azole-resistant strains of the fungus Aspergillus fumigatus have begun turning up more frequently in hospitals.
Unlike drug-resistant bacteria, which can spread from person to person, A. fumigatus is always picked up environmentally. There’s no documented case of anyone getting sick by breathing in Aspergillus exhaled by an infected patient, says Momany. Because of this, fungal researchers suspected A. fumigatus was evolving azole resistance in the field, rather than in patients. Still, there was no way to know for sure that it wasn’t caused by hospital drugs.
From “Big Chicken” to Big Tulip
“The idea came to me when I was reading the book Big Chicken by Maryn McKenna,” says Brewer. In the book, scientists showed that antibiotic-resistant bacteria had moved from chickens to humans – not the other way around – by showing that bacteria isolated from people contained genetic evidence of resistance to compounds used only in chickens. Brewer decided to apply that same logic to Aspergillus. “I thought it would be interesting to look for the signatures for resistance to fungicides only used in agricultural environments,” she says.
The researchers analyzed 700 different isolates of A. fumigatus collected from compost heaps, soil samples, and plant debris from 56 sites around Georgia and Florida. They sequenced and analyzed the genomes of 135 of these isolates. Most of the sites had a history of azole fungicide use, but two were organic sites with no fungicide use for 10 years. They also analyzed publicly available genome data of A. fumigatus samples from the US, the UK, the Netherlands, and India that were resistant to multiple azole compounds.
They found that A. fumigatus in the environment that carried resistance to azole compounds had often developed resistance to two other classes of fungicides used only in agriculture, benzimidazoles (MBC) and quinone outside inhibitors (QoI). Even more tellingly, A. fumigatus samples collected from patients carried the genetic markers indicating resistance to MBC and QoI.
“Those signatures showed that they were exposed to fungicides in an agricultural environment, and we’re finding them in strains from patients in hospital environments,” says Brewer.
The first hint that agricultural fungicides might be a problem in hospitals came from the Netherlands, the world’s major supplier of tulips and other ornamental flowers. “It turns out a tulip bulb is a wonderful place for fungi to grow,” Momany says. “Nobody wants decorative flowers with mold spots on them. To prepare these for shipping, they’re treated with azoles.” Discarded plant matter from these industrial tulip farms, she says, can spread azoles into the surrounding environment. Strikingly, Momany points out, A. fumigatus isn’t even dangerous to plants. It’s not the intended target of agricultural azole use, but because it’s so widespread, it gets exposed incidentally. “Once those azoles are in the environment, then the A. fumigatus that’s there develops its own resistance,” she says.
People are likely to encounter azole-resistant A. fumigatus in compost or in flower beds. “Compost is definitely a hot spot for Aspergillus that’s azole resistant,” says Brewer. “People who are immunocompromised should be very careful around compost, flower beds, or dusty areas where there can be a lot of fungi.”
This study is one of the first to characterize a fungal pathogen that has picked up antifungal resistance in an agricultural setting and carried that resistance into the clinic. “There could be a lot of others, and people just haven’t looked,” Brewer says.
Evidence for the agricultural origin of resistance to multiple antimicrobials in Aspergillus fumigatus, a fungal pathogen of humans
S. Earl Kang, Leilani G. Sumabat, Tina Melie, Brandon Mangum, Michelle Momany, and Marin T. Brewer
G3: GENES|GENOMES|GENETICS February 2022, jkab427