An agricultural fungicide that has been approved in the US and is currently being considered by authorities worldwide could have a devastating impact on a groundbreaking new drug for one of the deadliest infectious diseases in the world, according to scientists from the University of Manchester.
The researchers, funded by the Wellcome Trust, have published a study in Nature Microbiology that reveals the potential danger to patients with aspergillosis, a dangerous fungal disease that has caused millions of deaths globally.
Due to limited treatment options, aspergillus has developed widespread drug resistance to a class of drugs called azoles. This resistance is caused by the use of fungicides in agriculture, known as DMIs, which has increased the mortality risk from aspergillosis from 40% to as high as 80%.
However, a spin-out company from the University of Manchester called F2G Ltd has invested over £250 million in developing a new antifungal drug called olorofim. The drug is currently in late-stage clinical trials and aims to be available for clinical use within the next few years. Olorofim is effective against azole-resistant infections, potentially saving the lives of many affected patients.
Unfortunately, a newly developed fungicide crop spray called ipflufenoquin, which has been approved for use in the USA under the trade name Kinoprol, could severely impact the effectiveness of olorofim. This is because ipflufenoquin targets the same biological mechanisms and kills the fungi in the same way as olorofim.
Exposure of the aspergillus fungus to Kinoprol in the environment could make it resistant to olorofim, rendering the new treatment ineffective before it can even be used in clinics, warn the scientists.
The research team conducted laboratory experiments exposing aspergillus to ipflufenoquin and assessed its resistance to olorofim. They found that genetic mutations that cause changes in the antifungal target gene provide resistance to ipflufenoquin, but also confer resistance to olorofim.
Scientists have long been aware that the environmental use of fungicides, necessary for protecting crops from fungal infections, has the potential to drive resistance to other clinical antifungals.
Furthermore, the researchers believe that the composting of agricultural waste is leading to the accumulation of fungicides in environments where aspergillus thrives. Wind currents, intensive farming, and the transport of commercial composts can disperse drug-resistant fungal spores further into the environment, potentially reaching our gardens, bedrooms, kitchens, and bathrooms.
While most healthy individuals are unaffected by aspergillus, population groups such as the elderly, cancer patients, and immunosuppressed individuals of all ages are at a higher risk of serious illness and lung damage caused by the fungus.
Dr. Norman van Rhijn, the lead author of the study and a Wellcome Trust research fellow at the University of Manchester, expressed concern about the potential impact on olorofim. He emphasized the urgent need for a risk assessment strategy to address the dual use of antifungals in agriculture and clinics.
Professor Mike Bromley, the corresponding author of the study and a former employee of F2G Ltd, called for appropriate legislation to prevent the release of fungicides without considering the risks of driving drug resistance in human pathogens. He highlighted the efforts made in developing olorofim and the need for more robust risk assessments in the licensing of new agricultural antifungals.
The issue was recently debated in the UK’s House of Lords, with politicians raising concerns about the long-term impact of agricultural fungicide use on food and biological security. They emphasized the need for integrated and responsible legislation to address the impact of the climate emergency on public health and the National Health Service.
The study, conducted independently with F2G Ltd only assisting in a single assay, provides valuable insights into the potential risks associated with the use of fungicides and the development of drug resistance in fungal pathogens.
