By Angus Dalton
Examine, a free weekly newsletter covering science with a sceptical, evidence-based eye, is sent every Tuesday. You’re reading an excerpt – Sign up to get the whole newsletter in your inbox.
In the hazy period around Christmas and New Year’s Eve, when inboxes are supposed to be barren and life free from woe, Sydney infectious disease specialist Justin Beardsley received an urgent email from a globally renowned mycologist.
The fungi expert, Professor David Denning from the University of Manchester, had spent two decades working on a new antifungal drug that could treat Aspergillus fumigatus infection, which kills at least half a million people a year.
A fungicide used to protect strawberries from mould could render a new antifungal drug useless before it even hits the market.Credit: Matthew Absalom-Wong
The drug, olorofim, was on the cusp of being approved in the US by the Food and Drug Administration. But in a twist of dreadful timing, an agricultural fungicide that works the same way as olorofim hit the market first.
Denning feared the mass use of the chemical in agriculture would spur the evolution of drug-resistant fungi and render olorofim useless. He was campaigning against the registration of the fungicide in the UK.
But, Denning wrote to Beardsley, it appeared to be too late for Australia. The fungicide, ipflufenoquin, had already been approved in February 2023 and the first product containing the chemical was cleared for use soon after to kill grey mould on farmed strawberries.
Beardsley, who is part of a concerned society called the Australia and New Zealand Mycology Interest Group, has seen olorofim cure drug-resistant infections during clinical trials at Westmead Hospital.
Although he is unsure how widely used the fungicide is in Australia, he says rolling it out before the drug becomes commonly available is “like handing the enemy the weapon in advance before the battle”.
And this episode underscores a deeper crisis: as infectious fungi and deadly bacteria evolve to resist our medicines, pharmaceutical companies are giving up on crafting new drugs to kill them.
Fungal disease: hard to treat and on the rise
Earlier this year, Denning estimated in The Lancet that global deaths caused by fungal disease had almost doubled within a decade to 3.8 million annually – that’s 6.8 per cent of all deaths, a little more than smoke-related lung disease.
All of us have probably inhaled Aspergillus spores – they’re ubiquitous from cities to farms. But fungal infection takes hold only in the immunocompromised. As lifespans lengthen and there are more of us who are older and sicker, these infections are becoming increasingly common.
Some scientists think it’s also becoming easier for fungal infections to thrive within human bodies because fungi are evolving to suit a world growing hotter due to the burning of fossil fuels. (That includes that guy in the first scene of The Last of Us. Yikes.)
And fungal infections are tough to treat. Fungi cells are more similar to human cells than bacteria or viruses, so what’s toxic to fungi is often toxic to us. That restricts the number of medicines we can make to kill infectious fungi in the body; there are only four major classes of antifungal drugs compared to more than a dozen classes of antibiotics.
“Olorofim is unusual in that it’s a completely new drug class,” says Beardsley, an associate professor at the Sydney Infectious Diseases Institute at the University of Sydney. “Which is why it’s even more critical that we should try to protect it.”
Storm in a petri dish
A recent lab study proved the fears around olorofim well-founded. Researchers took Apsergillus, exposed it to the fungicide ipflufenoquin, and watched as the fungus quickly mutated to resist olorofim – a drug that cost at least £250 million ($476 million) and 20 years to develop.
The drug and the fungicide both target the same enzyme within fungal cells, which is why Aspergillus strains that evolve to become resistant to the crop spray also become immune to olorofim.
“When we found out that regulatory approval was sought for ipflufenoquin and its mode of action was the same as olorofim, we immediately felt alarmed,” says the lead author of the Nature Microbiology research, Dr Norman van Rhijn,.
Australia was one of the first countries to approve ipflufenoquin. Consultation on the fungicide was over and done with before van Rhijn’s study, and the potential impact of the crop spray on antifungal drugs was never raised with the Australian Pesticides and Veterinary Medicines Authority (APVMA).
The art and the artist; Aspergillus grown from samples gathered in Vietnam and Associate Professor Justin Beardsley, an expert in infectious diseases and fungi.Credit: Associate Professor Justin Beardsley
“Ideally, we would like to see a pause on the registration until the risk can be properly assessed,” Beardsley says. “It’s not like there aren’t other agricultural antifungals that can be used to make sure your berries are pristine.”
A spokesperson for the APVMA said: “Should evidence emerge in relation to a role for a substance to contribute to antifungal resistance, the APVMA would take that into consideration in determining appropriate regulatory action.”
Beardsley feels like he’s seen this all before. He is studying the rise of resistance to azoles – another precious class of antifungal medicines – driven by agricultural fungicides.
Ten years ago, there was no resistance. Now, in places such as Vietnam, 90 per cent of the Aspergillus strains sampled from rice paddies, fruit farms and even urban areas are resistant to azoles.
And the bad news is, a drug-resistant fungus can be twice as deadly if it infects a human.
More resistance, less drug research
This saga highlights a deeper problem. Drug resistance renders antibiotics and antifungals less profitable – so big pharmaceutical companies are backing away from making new ones.
“Most of the big pharmaceutical companies have massively reduced their investments in antibiotics and antifungals of all types,” Beardsley says.
“For drug companies to spend the millions and millions on development for an agent that may become obsolete within a year or two because of the emergence of resistance is not a good business model.”
The World Health Organisation has labelled the lack of new antibiotics and antifungals a crisis. Along with other agencies, it is campaigning for new ways of funding drug discovery because, as Beardsley says, the old model is “broken”.
The case of olorofim – which was developed by a small company spun out from the University of Manchester rather than by a pharmaceutical giant – underscores the challenges of bringing new anti-infectives to market and why big pharma is hesitant to invest.
Says Beardsley: “If you were Pfizer or AstraZeneca looking at this, you’d think, well, there you go – that’s proof that we were right.”
Examine, a free weekly newsletter covering science with a sceptical, evidence-based eye, is sent every Tuesday. You’re reading an excerpt – sign up to get the whole newsletter in your inbox.