By Kaitlin Sullivan
—
NBC News
Last summer, the Food and Drug Administration (FDA) denied the application for a new antifungal drug called olorofim, sending it back to the company and requesting more data.
If approved, it would have been the first time since the early 2000s that the FDA authorized an entirely novel antifungal.
The world faces a time when these medicines are critical: in recent years, the danger of fungal infections to human health has become increasingly evident, as
fungi evolve to evade existing treatments
or outrun their geographic regions. typical.
Doctors around the world are desperately searching for new drugs to combat this growing threat.
“The problem with fungal diseases has reached the point that the World Health Organization (WHO) has recognized it as a widespread threat,” said Arturo Casadevall, a microbiologist and professor of molecular microbiology and immunology at the Bloomberg School of Public Health. from Johns Hopkins, in Baltimore.
In late 2022, the WHO published its first list of priority fungal pathogens: 19 fungi that the agency says pose a significant threat to human health.
These include the
highly drug-resistant fungus
Candida auris , which infects hospitalized patients in critical condition.
In 2021 alone, the number of infections tripled in the United States, according to the Centers for Disease Control and Prevention.
[CDC warns that a virus that can cause serious illness in babies has spread to several states]
Also on the WHO list is
coccidioides
, a fungus that causes an infection called Valley fever.
Historically present in the southwestern US, scientists have predicted that its range could extend north to the Canadian border and east to the Great Plains by the end of the century.
The situation is complicated by the impact that fungi can have on the global food system.
Fungi thrive in soil and fungal diseases have long been a major problem in agriculture: up to a quarter of the world's crops are lost to fungal diseases before they are harvested.
Another 20% succumb to fungi after harvest.
Just as doctors use antifungals to treat infections in humans, farmers use fungicides, a type of pesticide, to kill fungal diseases that affect crops.
But fungicides can render critical antifungal medications useless.
[At least two cases of antibiotic-resistant ringworm detected in the US]
This is because many fungicides have the same molecular target as antifungals, 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 a fungicide intended 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 infect humans, they already have the ability to evade the antifungal that attacks them.
This scenario is not hypothetical.
Scientists have linked commonly used fungicides to increasingly drug-resistant infections caused by a fungus called
Aspergillus fumigatus
in 40 countries, including the United States.
Experts find it worrying that this fungus has developed resistance to an entire class of antifungals called azoles, the type of drug most prescribed for fungal infections.
In addition to treating a wide range of infections, it is 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 necessary to completely clear an infection.
“There are only three classes of antifungals left, and one of them is the azoles,” said Norman Van Rhijn, a researcher in the Fungal Infections Group at the University of Manchester (United Kingdom).
[Fungal outbreak at Michigan paper mill infects nearly 100 workers]
Several new drugs are also in play, such as olorofim, which is part of a new class of drugs and has been shown to be effective against azole-resistant Aspergillus.
“We don't want to paint this as a conflict between medicine and agriculture,” said Leah Cowen, professor of molecular genetics at the University of Toronto.
“It's not that we need antifungals for one thing more than the other, we need both types, but with different objectives.”
Need for new antifungals
Humans are much more closely related to fungi than to bacteria and viruses: we share approximately half of our DNA with fungi, and many proteins that are essential for them to survive are also essential for human cells.
This makes it very difficult to find a molecular target in a fungal cell that can be attacked without also causing serious damage to a human cell, which is why many antifungals have serious side effects, Van Rhijn explained.
Additionally, fungi can develop resistance to a drug very quickly.
Like viruses and bacteria, they have the innate ability to reproduce rapidly and mutate, and these mutations can give rise to strains that make drugs ineffective.
[Throat infections are increasing in children and there is a shortage of antibiotics to cure them]
This is also true in the world of bacteria and antibiotics—antibiotic resistance is another major threat to public health—but doctors still have many more antibiotics to choose from.
“We only have three major classes of antifungals to treat invasive infections, compared to several dozen classes of antibacterials,” Cowen said.
Those available are not perfect, he added.
“Some are toxic, others are susceptible to generating resistance and others have a limited spectrum of activity.”
Anna Selmecki, associate professor of microbiology and immunology at the University of Minnesota Medical School, was blunt about the urgent need for more drugs that can effectively combat fungi.
“I am concerned that many patients will die because our current set of antifungal drugs is limited and there are increasingly more fungi resistant to the few antifungals available,” Selmecki said.
Treatments in development
It takes about 25 years to develop a new antifungal, and the same amount to create a new fungicide, Van Rhijn explained.
So far, scientists have only identified a handful of viable molecular targets in fungal cells, and they are often the same target used in both antifungal drugs and fungicides.
In the case of the new drug olorofim, it is 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, licensed ipflufenoquine as a fungicide nearly two years ago.
[Eye drops contaminated with deadly bacteria have caused nearly 70 infections in 16 states]
Since the FDA requested more data on olorofim from the British pharmaceutical company F2G, Inc., the new antifungal is in phase 3 of 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, which has been linked to organ transplants.
“Olorofim is probably the most promising antifungal,” said Dallas Smith, an epidemiologist with the CDC's Fungal Diseases Branch, noting that the drug has been shown to be effective against “almost all fungal infections.”
Both treatments have the same target: an enzyme called dihydroorotate dehydrogenase.
According to Van Rhijn, there are other antifungals in the development phase that behave like olorofim.
He worries that a new antifungal called fosmanogepix, which has not yet been approved by the FDA, could be threatened by a pesticide called aminopyrifene—effective against a type of fungus that invades berries like strawberries—that acts on the same target.
Cowen agreed.
“The same story is repeating itself,” she said.
More cooperation to find new treatments
Competition with fungicides is not the only cause of antifungal resistance.
Poor diagnostic testing, poor infection surveillance, and drug misuse—fungal infections are often misdiagnosed—also play a role, but more coordinated monitoring of new drugs and pesticides and their targets will play a role. important to preserve the effectiveness of antifungals in the future.
This means that regulatory agencies like the FDA and EPA will have to work together when approving new drugs and fungicides.
“We have to balance the global food supply with antifungals for human use, and to do that we need more cooperation,” Smith said.
With careful planning, there will be room for both olorofim and ipflufenoquine, as well as other antifungals and fungicides with the same goals, he said.
“We know that not all infections will be intrinsically resistant to older antifungals.”
In September, the EPA announced that it was working with the Department of Health and Human Services and the Department of Agriculture on new guidelines that would better safeguard antifungals.
Remmington Belford, EPA press secretary, told NBC News in an emailed statement that the agency hopes to finalize that proposal by the end of this year.
Once finalized, the proposal will provide guidance for collaboration between agencies concerned with human health and the EPA, which approves pesticides, and on how pesticides can be evaluated for any potential antimicrobial resistance threats they may pose. pose.
[The dangerous super-drug-resistant fungus spreading through US hospitals]
Cowen said that even without such a framework, potentially life-saving antifungals should not be abandoned because of the risks that new fungicides pose to antifungal effectiveness.
“We continue to desperately need this new class of antifungals.
Olorofim has great potential to treat fungal infections for which we currently have no treatment,” he stated.