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 – a spin out company from The University of Manchester – invested more than £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 – which farmers need to keep their crops free of fungal infection – 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: “We 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.

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

“But it is desperately needed, as the few classes of drugs for Aspergillus infection available at present don’t give all of the seriously ill patients a viable treatment option.

“That 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.”

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: “It 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.

“We 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’s current agricultural fungicide use will affect long-term food and biological security.

Baroness Bennett, a former leader of the Green Party, told the chamber: “Managing 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.

“We need integrated, “one health” considerations of the impact of the climate emergency and responsible fungicide legislation.”

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

With the return of hosepipe bans in the UK and severe drought currently affecting many parts of Europe and elsewhere in the world, it's more important than ever to understand how we can grow more food while minimising pressures on freshwater resources and ecosystems.

To this end, the at The University of Manchester and are launching AquaPlan. AquaPlan is an interactive web tool that allow users to quickly and easily assess how crop yields and water demands are affected by different management practices and climate scenarios anywhere in the world.

Dr Tim Foster said: “Crop models are incredibly powerful tools to help agriculture adapt to growing pressures posed by water scarcity and climate change. However, these models require a lot of time and specialist expertise to implement which has often limited their use outside of research projects. AquaPlan provides a practical tool to overcome these challenges, putting state-of-the-art modelling tools in the hands of farmers, practitioners, and policymakers working to improve food and water security globally.”

AquaPlan combines a proven scientific modelling tools, automated data integration, cloud processing, and an intuitive interface to support real-world agricultural water management and climate adaptation. Under the hood, AquaPlan leverages an open-source crop-water model, , developed over the past 10 years by researchers in the at The University of Manchester in collaboration with the Food and Agriculture Organization of the United Nations (FAO).

The tool is ideally suited for regions where water is a limiting factor in crop production, an increasing problem facing food systems all around the world. AquaPlan enables users to automatically integrate weather and soil data from trusted open-source datasets and view model outputs in an accessible and interactive interface, all with just a few clicks in the browser. The result is a powerful tool that provides farmers, agronomists, water managers, and other end users with crop modeling capabilities previously only accessible to highly trained researchers and scientists.

In the coming months, the team will be adding more features within AquaPlan to support a range of uses of the tool in real-world agricultural climate risk and water management, including the ability to further customize simulations and implement AquaPlan over larger regional areas. If you are a potential user and have recommendations or requests for the development of AquaPlan, then the team would be delighted to hear from you. Get in touch by emailing Tim Foster (timothy.foster@manchester.ac.uk).

More in-depth information about Aquaplan is detailed in a new blog available via .

The discovery published in Current Biology shows that the fruit trees, which develop rubbery branches when infected, mirrors how scientists are trying to  genetically modify trees.

Apple rubbery wood virus (ARWV) -which causes apply rubbery wood disease - is now largely, if not totally, eliminated from commercial apple trees.

However, an extensive survey in the UK during the 1950s when ARWV was widespread revealed that in some cases, over 50% of apple trees sampled were infected with the virus

The widespread  presence of the virus  across the globe is well documented.

Though their branches become more flexible, no adverse effects to humans who have eaten fruit from the infected trees have been recorded and there have been no adverse environmental consequences..

Funded by the , the study also provides important insight into how scientists might one day be able to process woody plant tissue so that it efficiently produces sugars needed for biofuels.

Woody plant material represents a vast renewable resource that has the potential to produce biofuels and other chemicals with more favourable net carbon dioxide emissions.

However, scientists haven’t yet worked out an efficient way to release its substantial store of sugars estimated to be at around 70%.

The scientific team showed  that the symptoms of ARWV infections arise from a reduction in  lignin - a complex organic polymer that forms key structural material supporting the tissues of most plants.

Using next generation sequencing (NGS)  to analysis the expression of all the genes in the rubbery apple tree branches, they discovered that phenylalanine ammonia lyase (PAL), an enzyme responsible for lignin biosynthesis was suppressed.by the plant in response to the infection

The response to ARWV infection results in the plant generating a multiple ‘small interfering RNAs, known as (vasiRNAs)

The vasiRNAs then target several of the plants own genes to be downregulated-  or degraded-   in what is assumed to be part of an antiviral defence response.

One of the genes downregulated by the plant is PAL and this leads to the decrease in lignin biosynthesis that gives the increased flexibility of the branches and facilitates the release of sugars.

The mechanism used by the apple rubbery wood virus  to alter lignin closely resembles how scientists have  been altering lignin in genetically modified trees to make it easier to process.

Despite the altered lignin the trees manage to grow normally.

Lead author Professor Simon Turner said: “Widespread genetic engineering of many plants is limited by regulatory hurdles and public opposition, and this appears particularly true for trees. These research findings offer an important contribution to that debate.

“It is apparent from our work that technologies considered as new and under regulatory oversight exhibit similarities to events considered to occur naturally.

“It seems that unbeknown to us, the ARWV infections have been performing something akin to a huge field trial”

“Since the disease has been present across the globe for many decades, even conservative estimates would suggest that many thousands of infected apple trees were propagated.

“Millions of apples from ARWV-infected trees were eaten with no known adverse health or environmental consequences despite the siRNA-induced alterations in lignin caused by the plant’s response to the virus.”

He added: “Currently, the biofuel industry uses huge areas of agricultural land to  produce corn starch that is used to generate 60 Billion litres of bioethanol.

“That’s relatively inefficient in terms of CO2 savings, but may also impact on global food production systems.

“But our increased understanding of this mechanism may one day unlock the potential to isolate the sugars within the woody tissue, making the production of biofuels much more efficient.”