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An agricultural fungicide approved in the US and currently under consideration by authorities worldwide could have a devastating effect on a new drug for one of world鈥檚 deadliest infectious diseases, show University of Manchester scientists.

Their Wellcome Trust funded study, published in Nature Microbiology could spell disaster for patients with aspergillosis - a dangerous fungal disease responsible for the deaths of millions of people worldwide.

With few treatment options for patients, aspergillus has developed widespread drug resistance to one class of drugs, known as the azoles.

The resistance is caused by the use of fungicides in agriculture, known as DMIs, increasing the risk of mortality from aspergillosis from 40% to up to 80%.

However, F2G Ltd 鈥� a spin out company from The University of Manchester 鈥� invested more than 拢250 million over 20 years on a new antifungal drug called olorofim, which is in late-stage clinical trials and aims to be clinically deployed within the next few years.

The scientists argue that because olorofim works against azole resistant infections it could save many lives of affected patients.

However, a newly developed fungicide crop spray called ipflufenoquin has been approved for use in the USA, under the trade name Kinoprol, and could severely impact on the new drug because it has the same biological target and kills the fungi the same way as olorofim.

Exposure of Aspergillus in the environment to Kinoprol could make it resistant to olorofim, rendering the treatment ineffective before it can even be deployed in the clinic, say the scientists.

The research team exposed Aspergillus to ipflufenoquin in the lab and then assessed resistance to olorofim. Genetic mutations that cause changes in the antifungals target gene provide resistance to ipflufenoquin but also provide resistance to olorofim.

Scientists have long known that environmental use of fungicides 鈥� which farmers need to keep their crops free of fungal infection 鈥� has the potential to drive resistance to other clinical antifungals.

Researchers also believe that composting of waste from farms is causing accumulation of fungicides in environments where Aspergillus likes to grow.

Wind currents, intensive farming, and transport of commercial composts can disperse the drug-resistant fungal spores further into the environment and end up in our gardens, bedrooms, kitchens, and bathrooms.

Most healthy people are unaffected by Aspergillus, but population groups including the elderly, cancer patients, and the immunosuppressed of all ages are at greater risk of serious illness which destroys the lungs.

Lead author , a Wellcome Trust research fellow at The University of Manchester said: 鈥淲e are all very excited about olorofim but when we found out that regulatory approval was sought for ipflufenoquin and its mode of action was same as olorofim, we immediately felt alarmed.

鈥�Making a novel fungicide for humans is very difficult and costs millions of pounds.

鈥淏ut it is desperately needed, as the few classes of drugs for Aspergillus infection available at present don鈥檛 give all of the seriously ill patients a viable treatment option.

鈥淭hat is why olorofim is such an exciting prospect for patients and why we must lobby the regulatory authorities to implement a risk assessment strategy for the dual use of antifungals in agriculture and clinic.鈥�

But indirect implications to human health are not taken into account during the approval process, which is why researchers, collaborators, and clinical teams are lobbying hard for the authorities to risk assess any new fungicide.

Corresponding author Prof Mike Bromley, who is a former employee of F2G Limited and co-lead of the Fungal AMR and One Health Network, said: 鈥淚t is devastating that the efforts that so many have made in development of olorofim are being put at risk by the lack of appropriate legislation that would prevent the release of fungicides without consideration of the risks to driving drug resistance in human pathogens.

鈥淲e have made our views clear to the Environmental Protection Agency in the USA and hope they will re-evaluate their approach to environmental release of fungicides.

Politicians in the House of Lords recently a question by Baroness Bennett of Manor Castle, which asked the Government what assessment they made of how the UK鈥檚 current agricultural fungicide use will affect long-term food and biological security.

Baroness Bennett, a former leader of the Green Party, told the chamber: 鈥淢anaging fungal crop disease has always been essential to our ability to feed the population, but we cannot afford a haphazard, piecemeal approach that will hurt our public health and our NHS.

鈥淲e need integrated, 鈥渙ne health鈥� considerations of the impact of the climate emergency and responsible fungicide legislation.鈥�

Baroness Hayman of Ullock and Baroness Walmsley also spoke in the debate, and highlighted the specific case of olorofim and ipflufenoquin as they called for more robust risk assessments in the licensing of new agricultural antifungals.

• F2G carried out a single assay in the study that the researchers would otherwise have not been able to facilitate. However, the vast majority of the study was carried out independently.
• The paper Aspergillus fumigatus strains that evolve resistance to the agrochemical fungicide ipflufenoquin in vitro are also resistant to olorofim is available