Fungal resistance: An under-recognised crisis with massive global impact.

Antifungals - the deadly cycle from field to clinic

Fungal diseases affect billions of people and estimates suggest they are responsible for around two million deaths per year worldwide. 

Only four main classes of antifungal drugs are approved to treat invasive fungal diseases, and they are developing resistance in real time. Fungi are also the main agents of disease threatening the world’s crop supplies. The same classes of drug are used to treat plant and human fungal infections, resulting in a cycle that links farmers’ fields with hospital wards.

This massive global challenge has medical, biological, ecological, social, legal and humanities elements which requires broad multidisciplinary action. All of which come together under Exeter’s One Health approach which includes researching new compounds to protect crops, innovating in gene editing, and creating new ways to diagnose potentially fatal infections early. Exeter researchers are part of a research collaboration to create a One Health Road Map, which seeks to chair inter-related actions across the world to mitigate the growing risk of anti-fungal resistance.

In the last four years, Exeter’s Medical Research Centre Centre for Medical Mycology (MRC CMM) has launched research units in South Africa and Brazil, facilitating collaboration across the globe.

They are tackling fungal diseases endemic to the geographical regions in which they are located and bringing together interdisciplinary research.

Clinical Mycology is also one of five core themes of the NIHR Exeter Biomedical Research Centre, which overlaps with MRC CMM and aims to accelerate the translation of scientific discoveries into patient benefits.

The Centre’s also working with the UK Government’s Department for Health and Social Care Global AMR Innovation Fund to deliver a £3.4M fund called FAILSAFE (Fungal AMR Innovations for LMICS: Solutions and Access For Everyone) to support researchers working on solutions for antifungal resistance.

Part of the solution lies in finding new ways to protect crops. Fungal infections cost the agricultural industry £4-8 billion in losses, decimating up to half a harvest. One of the most serious pathogens to infect wheat is caused by the fungus Zymoseptoria tritici, causing leaf blotch. UK growers alone lose around £200 million per year in wheat yield due to this disease. 

At Exeter, Professors Gero Steinberg and Sarah Gurr have developed a new type of fungicide. Instead of targeting a specific enzyme, their approach fights antifungals by inhibiting multiple processes in the fungus at the same time, so that it is much harder for them to evolve resistance. The new potential fungicide works by targeting mitochondria – the ‘powerhouse’ of cells – where it interferes with the production of chemical energy. Crucially, the fungicide does not bind to a specific target enzyme, thereby making the development of resistance unlikely. Moreover, the new compound appears to be of low toxicity to humans, water organisms and of no toxicity to plants.

How an environmental fungus became a threat to human health

In clinic, Professor Adilia Warris reported one of the first cases of a boy in whom antifungal resistance was detected to the mould Aspergillus fumigatus – a fungus that mainly caused disease in the lung.

We routinely inhale the tiny spores of the airborne mould Aspergillus fumigatus – usually with no ill effect for people with healthy immune systems. However, for patients with compromised immunity, the fungus can be deadly. Invasive aspergillosis is an important cause of death in acute leukaemia and bone marrow transplant patients, accounting for more than 300,000 life-threatening infections each year, with an associated mortality rate of 50 to 90 per cent. 

Professor Warris studied how Aspergillus fumigatus could also adapt to the antifungal treatment in individual patients in hospital. The pathogen was initially susceptible to treatment but developed resistance and stopped working after around two months. 

“We were the first to use the new gene editing technique CRISPR Cas-9 in clinical Aspergillus fumigatus isolates,” Professor Warris explained. “It enabled us to cut out a specific part of the fungal DNA and replace it. We can then see if the resistance resolves or becomes more susceptible. We discovered a new mutation in Aspergillus fumigatus which was induced by using azole anti-fungal drugs in this patient. These kinds of discoveries help us learn what’s driving antifungal resistance and what could be new targets for antifungal drugs.” 

A key issue is that Aspergillus infections are difficult to diagnose, and diagnosis too late to save the patient, with some infections at up to 90 per cent fatality if treated too late. Early diagnosis is crucial to save lives.  

To address this issue, Professor Chris Thornton, of the University of Exeter, has developed a simple £10/test, and a highly accurate lateral flow device for diagnosing Aspergillus. 

The test takes minutes and can be done anywhere and will tell doctors if they are fighting a fungus, not a bacterium or virus. This test has been used in more than 30 countries, giving clinicians the best chance of prescribing appropriate drugs which is often a case of saving the patient’s life.

Professor Thornton has also developed a lateral-flow device for mucormycosis, the second most common mould disease of humans after aspergillosis, and which surged during the second wave of the Covid-19 pandemic, especially in low- to middle-income countries (LMICs). This is the first time that a rapid antigen test has been developed for this highly aggressive angio-invasive disease caused by Mucorales fungi, pathogens which display intrinsic resistance to anti-fungal drugs. The ZygoLFD® test will enter clinical evaluation in Belgium, France and the UK in 2024, with commercial release by Professor Thornton’s University of Exeter spin-out company ISCA Diagnostics Ltd.  This cheap, rapid, accurate, and easy-to-use point-of-care test will be of particular benefit to doctors in LMIC countries where the majority of cases of life-threatening and disfiguring mucormycosis are seen, but where access to diagnostic testing facilities is absent or limited.

Exeter’s research is also having meaningful benefits for other fungal infections which are hard to treat. Chromblastomycosis is a chronic fungal skin disease. Seen worldwide, the infection is most prevalent in South America and other tropical or sub-tropical regions of the world. It causes unsightly skin legions, and often the only option is the painful and highly invasive surgical procedure of skin removal, combined with long term use of antifungals, which are often relatively ineffective.    

At Exeter, based on his understanding of immune recognition mechanisms of fungi, Professor Gordon Brown generated a new idea of how to boost the immune system. The non-invasive method simply involves applying an ointment, stimulating a missing component of the immune system and driving an enhanced immune response that can eliminate the fungus.

This works at least as well as painful skin grafts and means patients don’t need to take antifungal drugs for a long period – avoiding unwanted side effects, including liver toxicity and the development of resistance. This method is now the subject of a small clinical trial in Brazil and has potential in the treatment of other types of fungal infection. The same technique is being trialled by US scientists in the quest to eradicate ‘white nose syndrome’, which kills millions of bats each year. 

Professor Neil Gow said: “This wide range of interconnecting approaches exemplifies Exeter’s One Health approach. These diverse studies represent the holistic approach we are taking to the AMR challenge and illustrate how our discovery research is translating into research with impact.”