Mutant moulds threaten newest antifungal drugs putting immunocompromised patients at risk

Agrichemical use of antifungals has created moulds with a propensity to evolve resistance to novel drugs to treat fungal infections, including drugs not on the market yet.

The fungus in question, Aspergillus fumigatus, lives on decaying plant matter, but its spores can germinate in the lungs of immunocompromised people. Around 30 million people are at risk of contracting deadly infections from this fungus due to conditions such as chronic obstructive pulmonary diseases or cancer patients who are immunosuppressed.

Researchers now report that some azole-resistant Aspergillus harbour mutations in their DNA repair mechanisms that allow them to evolve faster. ‘All strains that were azole resistant were five-fold more likely to gain mutations that provide resistance to novel drugs due to altered DNA mismatch repair systems,’ says Michael Bottery at the University of Manchester, UK, who led the study. This could allow the fungus to quickly develop resistance to antifungals unknown to it including olorofim, a new drug that was developed by a spin-out company from the University of Manchester following investment of more than £250 million over two decades.

In some medical centres, 10% of Aspergillus infections are resistant to azoles, which is the first treatment of choice. Olorofim is in late-stage clinical trials and the hope is that it could save the lives of patients with infections resistant to existing antifungal drugs.

Azoles work by blocking an enzyme involved in making ergosterol, part of the fungal cell membrane. However, mutations in this enzyme in Aspergillus have, in the past, reduced the effectiveness of azoles.

Widespread application of agricultural antifungals has also led to stepped-up production of this target enzyme in some A. fumigatus isolates, with the enzyme then too abundant for the drug to be effective. The problem now identified is that some strains of A. fumigatus employ both of these strategies. ‘It seems that a subset of isolates has resistance to existing drugs piggybacked onto an elevated mutation rate,’ says Johanna Rhodes at Imperial College London, who was part of the research team.

‘Azole-resistant isolates are five times more likely to gain resistance to the new drug, olorofim,’ says Bottery. ‘This could essentially give rise to some strains resistant to all our medications.’ One unknown is how abundant the faster-evolving fungi are.

In 2023, the group reported that a new agrichemical fungicide – ipflufenoquin – boosts resistance to olorofim because it targets the same binding site on a mitochondrial enzyme.

‘We’ve got several choices to treat Aspergillus now, but the problem is that they have all been in the same class of antifungals,’ says George Thompson, a medical microbiologist at the University of California, Davis. ‘But there’s a number of new drugs approaching the market right now that look like they’ve got fantastic efficacy for Aspergillus.’ He names olorofin and fosmanogepix as examples.

‘This new study is troublesome because it shows isolates may easily develop resistance to new drugs, with strains that can rapidly mutate. That is bad news for even future drugs,’ says Thompson. ‘It flashes a warning light that we will need to pay attention to the development of resistance over the next five years.’

‘We really need to be very judicious in what we approve for veterinary use and for crops because it is going to affect our patients,’ he adds. ‘And we need all the regulatory agencies sitting at the table together.’