Aspergillus fumigatus conidiophore in microscopic view, featuring a swollen vesicle and conidia chains.
Image Credit: Scientific Frontline / AI generated
Scientific Frontline: Extended "At a Glance" Summary: Genetic Cross-Resistance in Aspergillus fumigatus
The Core Concept: Genetic hitchhiking in the pathogenic fungus Aspergillus fumigatus occurs when genes conferring resistance to medical antifungal drugs are co-selected with genes providing resistance to agricultural fungicides. This linkage allows non-medical fungicides to inadvertently maintain and promote fungal strains that are highly resistant to life-saving clinical treatments.
Key Distinction/Mechanism: Unlike simple, single-target drug resistance, this evolutionary mechanism involves multiple resistance genes being inherited together. Consequently, exposure to non-azole agricultural fungicides, which utilize completely different chemical structures and modes of action, still provides a survival advantage to azole-resistant fungi.
Origin/History: Clinical treatment with antifungal azoles has increasingly failed since the early 2000s, with approximately 10 percent of Aspergillus infections now caused by resistant strains. Recent research from Wageningen University & Research mapped the distribution of variants TR34 and TR46, linking agricultural fungicide use directly to the prevalence of medical drug resistance.
Major Frameworks/Components:
- Evolutionary Biology and Natural Selection: Agricultural environments treated with fungicides favor the fittest fungi carrying multiple resistance genes.
- Genetic Linkage and Hitchhiking: Distinct resistance genes are co-selected, meaning the use of one chemical indirectly selects for resistance against another.
- Cross-Class Enzyme Targeting: Both medical drugs (e.g., olorofim) and agricultural chemicals (e.g., ipflufenoquin) frequently target the same fungal enzymes, such as DHODH.
Branches of Science: Medical Mycology, Evolutionary Genetics, Molecular Plant Pathology, Environmental Microbiology, and Clinical Pharmacology.
Future Application: These findings highlight the need for systemic agricultural reforms and will guide the development of exclusive antifungal drug classes reserved strictly for human clinical use, ensuring they are never deployed in crop protection.
Why It Matters: Aspergillus fumigatus spores are ubiquitous in the environment, and inhalation can be fatal for immunocompromised individuals, such as cancer and organ transplant patients. Recognizing how agricultural fungicides sustain medical resistance is essential for preserving the efficacy of vital antifungal therapies.
Resistance to antifungal medicines in the pathogenic fungus Aspergillus fumigatus is proving more persistent than previously thought. Research by Wageningen University & Research (WUR) shows that fungicides used in agriculture, even those with a different mode of action from these medicines, can help maintain this resistance. This is because different resistance genes "hitchhike" together.
Microscopically, Aspergillus fumigatus is characterized by a conidiophore consisting of a stipe terminating in a swollen vesicle, which is covered by phialides producing chains of conidia. These microscopic spores spread through the air in vast numbers. The fungus naturally grows mainly in plant waste and compost heaps, where it helps break down plant material. However, people with weakened immune systems—for example, those undergoing cancer treatment or who have undergone an organ transplant—can become seriously ill if they inhale the spores. "Once someone develops a serious infection caused by this fungus, the outcome is unfortunately often fatal," explains Eveline Snelders, a medical mycology researcher at Wageningen University & Research.
Since the beginning of this century, treatment with antifungal medicines such as azoles has increasingly failed in patients infected with the fungus. The fungus has developed resistance. Around 10 percent of Aspergillus infections are now caused by a resistant strain. Snelders and her colleagues have discovered that the problem is even more complex than they previously thought, due to combinations of resistance mechanisms in Aspergillus.
The clinical management of A. fumigatus is increasingly challenged by two concurrent factors: a rising prevalence of azole-resistant isolates and an expanding population of immunocompromised individuals. Early in her research, Snelders discovered that the medical azoles used to treat Aspergillus infections are similar to the azoles used in agriculture to control other fungal species that threaten crops. The research team identified that agricultural azoles are structurally similar to medical azoles and are deployed in substantial volumes.
The agricultural and medical products target the same enzyme in the fungus. Hylke Kortenbosch, a PhD candidate supervised by Snelders, discovered that two resistant variants of Aspergillus, TR34 and TR46, differ in their distribution in the air across the Netherlands. TR34 was already found throughout the country, while TR46 was more common in agricultural areas with many flower bulb fields and greenhouses.
Now there is another cause for concern. These resistant variants of Aspergillus often also prove resistant to fungicides from two other chemical classes used in agriculture. These fungicides are not used in medicine, but they can still help maintain resistance to antifungal medicines. According to Kortenbosch, this makes the problem even more complex. "In agriculture, we are creating an environment in which natural selection favors the fittest fungi, those carrying multiple forms of resistance. The genes hitchhike together."
To model environmental exposure, researchers cultured resistant and susceptible A. fumigatus isolates on untreated organic plant matter (grass clippings) in closed glass microcosms, both with and without the application of specific fungicides.
The experiment showed that even fungicides that are not azoles gave azole-resistant fungi an advantage. The researchers conclude that banning azoles in agriculture alone would not be enough to solve the resistance problem quickly. Because different resistance genes hitchhike together, other fungicides can help maintain resistance to medical treatments.
For this reason, Snelders is deeply concerned about the development and use of new fungicides, including a new class that inhibits the enzyme DHODH. The antifungal drug olorofim is being developed to treat serious fungal infections, including those caused by Aspergillus. The agricultural fungicide ipflufenoquin targets the same enzyme. Snelders fears that the pattern of resistance development will repeat itself. "What you really want is to have a separate class of medicines reserved for treating Aspergillus infections in vulnerable patients, without that same class also being used in agriculture."
The researchers conclude that mitigating agricultural selection pressure is a critical factor in preserving the clinical efficacy of both current and future antifungal drug classes.
Published in journal: Current Biology
Authors: Hylke H. Kortenbosch, Spyros G. Kanellopoulos, Luisa Timmermanns, Francisca Reyes Marquez, Bas J. Zwaan, Ben Auxier, and Eveline Snelders
Source/Credit: Wageningen University & Research | Eveline Snelders, PhD MSc
Edited by: Scientific Frontline
Reference Number: bio110926_01