Emerging Super Moulds Challenge New Antifungal Treatments, Endangering Immunocompromised Patients

The agricultural usage of antifungals has led to moulds possessing an ability to develop resistance to new medications designed to combat fungal infections, including drugs that are not yet available on the market.

The fungus in focus, Aspergillus fumigatus, thrives on decomposing plant matter, yet its spores can proliferate in the lungs of vulnerable individuals. Approximately 30 million individuals are at risk of acquiring lethal infections from this fungus due to ailments such as chronic obstructive pulmonary disease or cancer treatment that suppresses the immune system.

New data from researchers indicates that various azole-resistant Aspergillus contain mutations in their DNA repair processes that enable them to adapt more swiftly. ‘All azole-resistant strains were five times more prone to acquire mutations that confer resistance to novel drugs because of altered DNA mismatch repair mechanisms,’ states Michael Bottery from the University of Manchester, UK, who spearheaded the research. This could empower the fungus to rapidly gain resistance to antifungals that are unfamiliar to it, such as olorofim, a new treatment developed by a spin-off organization from the University of Manchester after an investment exceeding £250 million over a span of two decades.

In certain healthcare facilities, 10% of Aspergillus infections exhibit resistance to azoles, which are typically the initial line of treatment. Olorofim is currently undergoing late-stage clinical trials, with hopes that it could safeguard the lives of patients dealing with infections resistant to existing antifungal therapies.

Azoles operate by inhibiting an enzyme crucial for the synthesis of ergosterol, a component of the fungal cell membrane. However, mutations affecting this enzyme within Aspergillus have, historically, diminished the effectiveness of azole treatments.

Widespread use of antifungal agents in agriculture has also resulted in increased production of this target enzyme in some A. fumigatus strains, leading to an overabundance of the enzyme that renders the drug ineffective. The current issue identified is that some A. fumigatus strains utilize both strategies for resistance. ‘It appears a subset of isolates possesses resistance to existing medications while being coupled with an elevated mutation rate,’ remarks Johanna Rhodes from Imperial College London, who participated in the research team.

‘Azole-resistant isolates are five times more likely to develop resistance to the new drug, olorofim,’ Bottery explains. ‘This could potentially lead to some strains being resistant to all available treatments.’ One variable remains unknown: the prevalence of these rapidly evolving fungi.

In 2023, the team reported that a new agricultural fungicide — ipflufenoquin — enhances resistance to olorofim due to its targeting of the same binding site on a mitochondrial enzyme.

‘We have several options to treat Aspergillus currently, but the drawback is that they all belong to the same class of antifungals,’ comments George Thompson, a medical microbiologist at the University of California, Davis. ‘However, there are multiple new drugs being developed and nearing market release that appear to demonstrate excellent efficacy against Aspergillus.’ He cites olorofin and fosmanogepix as examples.

‘This new research is concerning as it indicates that isolates may swiftly develop resistance to newly introduced drugs, particularly strains that can quickly mutate. This poses a significant threat even to future treatments,’ warns Thompson. ‘It raises an alert that we must closely monitor the evolution of resistance over the next five years.’

‘We must exercise caution in what we authorize for veterinary applications and crop utilization as it will impact our patients,’ he adds. ‘Moreover, we require all regulatory bodies to collaborate effectively.’