Last summer, the Food and Drug Administration denied an application for a new antifungal drug called olorofim, sending it back to the company with a request for more data. If approved, it would have been the first time since the early 2000s that the FDA cleared an antifungal that works in an entirely novel way.
It couldn’t come at a more important time: In recent years, the potential danger fungal infections pose to human health has become more and more apparent, as fungi either evolve to evade treatments or spread beyond their typical geographical regions. Doctors around the world are desperate for new medicines to combat the growing threat.
“The problem with fungal diseases has gotten to the point where the World Health Organization has recognized it as a widespread threat,” said Dr. Arturo Casadevall, a microbiologist and chair of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health in Baltimore.
In late 2022, the WHO published its first-ever list of fungal priority pathogens — 19 fungi the agency said pose a significant threat to human health. It includes the highly drug-resistant yeast Candida auris, which infects critically ill hospital patients; in 2021 alone, the number of infections in the U.S. tripled, according to the Centers for Disease Control and Prevention.
Also on the WHO’s list is coccidioides, a fungus that causes an infection called Valley fever. Historically found in the southwestern U.S., scientists have predicted that its range could spread north to the Canadian border and east to the Great Plains by the end of the century.
The situation is complicated by the impact fungi can have on the global food system.
Fungi thrive in soil, and fungal diseases have long been a huge issue in agriculture — as much as one-quarter of the world’s crops are lost to fungal diseases before being harvested. Another 20% succumb to fungi after harvest. Similar to the way doctors use antifungals to treat fungal infections in humans, farmers use fungicides, a type of pesticide, to kill fungal diseases that overtake crops.
But the much-needed fungicides can render critical antifungal drugs useless.
That’s because many fungicides have the same molecular target as antifungal drugs, including existing drugs, as well as some long-awaited new ones that are in the final stages of clinical trials. If a fungus is regularly exposed to fungicide meant to kill it — many fungi that can infect the human body also thrive in soil and decaying plant matter — it can develop resistance to it. If these mutated fungi then infect humans, they already have the ability to evade the antifungal that targets them.
The above scenario isn’t hypothetical. Scientists have linked commonly used fungicides to increasingly drug-resistant infections of a fungus called Aspergillus fumigatus in 40 countries, including the U.S.
Of particular concern is that the fungus has developed resistance to an entire class of antifungals called azoles, the most commonly prescribed type of drug for fungal infections. In addition to treating a wide range of infections, it’s also the only antifungal that can be taken at home and the only one that can be taken for more than six months, which is often required to fully clear an infection.
“We are down to three classes of antifungals, and one of them is the azoles,” said Norman Van Rhijn, a research fellow in the Manchester Fungal Infection Group at the University of Manchester in the United Kingdom.
Several new drugs also hang in the balance, including olorofim, which is part of a new class of drugs and that has shown to be effective against the azole-resistant Aspergillus.
“We don’t want to paint this as a conflict of medicine versus agriculture,” said Leah Cowen, a professor of molecular genetics at the University of Toronto.“It’s not that we need antifungals for one over the other, we need both, but with different targets.”
A need for new antifungals
Humans are much more closely related to fungi than we are to bacteria and viruses: We share about half of our DNA with fungi, and many proteins that are essential for fungi to survive are also essential for human cells.
That makes it very difficult to find a molecular target in a fungal cell that can be attacked without also causing severe damage to a human cell, which is why a lot of antifungals have serious side effects, Van Rhijn said.
On top of that, fungi can develop resistance to a drug very quickly.
Like viruses and bacteria, they have the innate ability to reproduce quickly and mutate, and those mutations can lead to strains that render drugs ineffective.
This also happens in the world of bacteria and antibiotics — antibiotic resistance is another major public health threat — but doctors still have many more antibiotics to choose from.
“We only have three major classes of antifungal drugs to treat invasive infections compared to several dozen classes of antibacterials,” Cowen said.
The ones that are available are less than perfect as it is, she added. “Some are toxic, some are susceptible to resistance and some have a limited spectrum of activity.”
Anna Selmecki, an associate professor of microbiology and immunology at the University of Minnesota Medical School, was blunt about the dire need for more drugs that can effectively combat fungi.
“I’m concerned that many patients will die because our current set of antifungal drugs are limited and more fungi are resistant to the few antifungal drugs available,” Selmecki said.
Competing targets
It takes about 25 years to develop a new antifungal drug, and a similarly long time to create a new fungicide, Van Rhijn said. Scientists have so far identified only a handful of viable molecular targets in fungal cells, and they’re often the same target used in both antifungal drugs and fungicides.
In the case of the new drug olorofim, it’s a fungicide called ipflufenoquin — used on fruit and nut trees and in vineyards. The Environmental Protection Agency, which reviews and approves pesticides independently of the FDA, cleared ipflufenoquin as a fungicide nearly two years ago.
Since the FDA requested more data on olorofim from British drugmaker F2G, Inc., the novel antifungal has been in phase 3 clinical trials. Studies so far have shown the drug to be effective against the fungus that causes Valley fever, as well as a rare emerging fungal infection called lomentosporiosis that’s been linked to organ transplants.
“Olorofim is probably the most promising antifungal,” said Dallas Smith, an epidemiologist with the Mycotic Diseases Branch of the CDC, noting that the drug has shown to be effective against “almost every single fungal infection.”
Both treatments have the same target: an enzyme called dihydroorotate dehydrogenase.
According to Van Rhijn, there are other antifungal drugs in the pipeline that are following the same trajectory as olorofim. He worries that a novel antifungal called fosmanogepix, which has not yet been FDA-approved, could be threatened by a pesticide called aminopyrifen — effective against a type of fungi that invades soft fruit like strawberries — that works on the same target.
Cowen agreed.
“The same story is playing out again,“ she said.
Can cooperation between agencies save antifungals?
Competition with fungicides is not the only issue driving antifungal drug resistance. Poor diagnostic tests, little surveillance of infections and drug misuse — fungal infections are often misdiagnosed — all play a role as well, but more coordinated oversight of new drugs and pesticides and their targets is going to play a significant role in preserving the effectiveness of antifungals moving forward. This means regulatory agencies like the FDA and the EPA will need to work together when approving new drugs and fungicides.
“We need to balance the global food supply with human antifungals, and we need more cooperation with that,” Smith said.
With careful planning, there will be room for both olorofim and ipflufenoquin, as well as other antifungals and fungicides with the same targets, he said. “We know that not all infections will be inherently resistant to the older antifungal medications.”
In September, the EPA announced it was working with the Department of Health and Human Services and the Department of Agriculture on a potential framework that would better safeguard antifungals. The agency expects to finalize the framework by the end of this year, Remmington Belford, the EPA press secretary, told NBC News in an emailed statement.
When finalized, the framework will provide guidance for collaboration between the agencies that deal with human health and the EPA, which approves pesticides, and how pesticides can be evaluated for any potential threats to antimicrobial resistance they may pose.
Cowen said that even without such a framework, potentially life-saving antifungals shouldn’t be dropped because of the risks the new fungicides pose to the antifungals’ efficacy.
“We still desperately need this new class of antifungals. Olorofim has great potential to treat fungal infections we currently don’t have treatments for,” she said.
