How our fungal research leads to parliamentary questions

18 April 2025

Just like bacteria, pathogenic fungi are increasingly becoming resistant to medication. However, while bacteria develop resistance within the human body, fungi acquire it somewhere else: in agriculture. So how does this happen, and what can we do about it?

Over the past thirty years, medical microbiologist Paul Verweij has collected more than 12,000 samples of the fungus Aspergillus fumigatus, mainly from lung tissue of patients in various hospitals suspected of having a fungal infection. Analysis of all these samples shows that over the years, the fungus has become increasingly resistant to medication, making treatment more difficult.

Spreading

For healthy people, the fungus is harmless. 'A. fumigatus helps decompose dead leaves in nature', Paul explains. 'The spores float through the air, and we inhale them daily. If you're healthy, your body clears them out. But in people with an impaired immune system, such as those with leukemia or in the ICU with severe flu, the fungus can grow in the lungs. In serious cases, it can spread through the lungs and even reach the kidneys or brain.'

Azoles are the first line of treatment, usually in pill form. There are two other medications available, but they can only be administered via IV. One has many side effects, and the other is not very effective.

Agriculture

In recent decades, resistance to these azoles has emerged. But not in patients, rather in agriculture. 'Agricultural azoles are used in food production and floriculture to combat fungal infections in crops', Paul explains. 'We found that especially in waste heaps from such production lines, A. fumigatus comes into contact with agricultural azoles. That's where the fungus develops resistance to agricultural azoles, making medical azoles inactive as well.'

Spores of these resistant fungi then enter human lungs through the air. The percentage of A. fumigatus strains resistant to azoles has risen to around ten percent over thirty years, severely limiting treatment options.

Sensitive

Fortunately, researchers in Manchester have been working for years on a new antifungal drug: Olorofim. Meanwhile, the final clinical trial required for market approval of this drug is underway. Radboudumc is also participating. The studies show that Olorofim works very well in infections with fungi that are resistant to azoles. In severe cases for which there are no more treatment options, the drug can already be requested outside of the clinical trials.

Medical microbiologist Jochem Buil collaborates closely with the company developing Olorofim. 'Because of our expertise, they asked us to test in the lab whether Olorofim also kills resistant A. fumigatus and other fungi', Jochem says. 'We tested over a thousand A. fumigatus strains and found that they were all sensitive to Olorofim. So it’s a very promising drug.'

Bottleneck

But on one of the Petri dishes containing Olorofim, the fungus still managed to grow. This strain turned out to be resistant to Olorofim. Jochem investigated how that was possible. It turns out the drug inhibits a gene in the fungus that prevents it from growing. But this fungus had developed mutations in that gene, rendering the drug ineffective.

The chance of such mutations occurring naturally is very low. But here's the bottleneck: a pesticide very similar to Olorofim, Ipflufenoquin, has been developed for agricultural use. It targets the same fungal gene and is used, for example, in almond farming to combat fungal spoilage. A Japanese company developed the product, and it’s already approved for use in agriculture in Australia and the US. It is currently under review in Europe.

Political agenda

'We purchased the fungicide from the company and tested its effects on azole-resistant A. fumigatus', Jochem explains. 'We found that it inhibits growth of A. fumigatus, but just like with Olorofim, resistance can develop. And fungi that became resistant to Ipflufenoquin also turned out to be resistant to Olorofim.' This means that, just like with azoles, resistance could develop to this promising new drug through agricultural use of a similar product.

Paul and Jochem are thinking ahead. 'With azoles, it took about ten years after introduction in agriculture before problems arose in the clinic', says Paul. 'It’s likely we’ll see the same pattern with Olorofim.' That’s why Paul is working hard to bring the issue of resistant fungi to the political agenda.

Bee mortality

Thanks to his fungal research, Paul frequently prompts politicians to raise questions in the Dutch Parliament. He was also involved in various reports on the topic, including those from the Health Council, European Agencies, the CDC in both Europe and the US, and the WHO. These reports primarily offer advice on assessing the risks of using similar products in agriculture and medicine.

'Currently, the authorities assessing new agricultural products only consider fungi that cause plant diseases, not the risk of resistance in fungi that affect humans, such as A. fumigatus', Paul explains. 'They only study the direct effects on humans and, for instance, bee mortality. It would be great if the approval process also considered the impact on fungi that cause human disease.'

Step-by-step approach

Paul doesn’t expect these substances will be entirely banned from agriculture or reserved exclusively for healthcare. Paul: 'The interests of food production are too great for that. But risk assessment and monitoring can already go a long way in preventing resistance.'

In the most recent report by the European Agencies, Paul and other specialists propose a step-by-step approach. The first question is whether a new substance is active against pathogenic fungi like A. fumigatus. Next, whether fungi can develop resistance to it and whether  resistance affects the activity of the medical product. Then it’s important to determine the concentration at which resistance develops and where in the production chain those concentrations might occur.

'If you map all of that, you’ll see, for instance, that resistance arises in a waste pile from an agricultural production line. You can then take targeted action to clean up that pile quickly', says Paul. 'In the meantime, it’s helpful if farmers reduce their use of such agents or replace them with alternatives, preferably biological ones. With this combined approach, we can keep agricultural pesticide use safe and preserve the effectiveness of our medications.'

 

Book tip: Want to learn more about the fascinating world of fungi? Entangled Life by Merlin Sheldrake explores the world from the fungi’s perspective.

 

This article appeared in Radbode, #2, 2025.

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