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The threat of fungal infections is increasing. Why is it so difficult to make new drugs?

Last summer, the Food and Drug Administration rejected an application for a new antifungal drug called olorofim, sending it back to the company with a request for additional data. If approved, it would have been the first time since the early 2000s that the FDA has authorized an antifungal that works in an entirely new way.

This couldn’t come at a more important time: in recent years, the potential danger of fungal infections to human health has become increasingly evident, as fungi evolve to evade treatment or spread beyond their native regions. usual geographic locations. Doctors around the world are desperately searching for new drugs to combat this growing threat.

“The problem of 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 released its first-ever list of priority fungal pathogens – 19 fungi that the agency says pose a significant threat to human health. It includes the highly drug-resistant yeast Candida auris, which infects critically ill hospitalized patients; In 2021 alone, the number of infections in the United States has tripled, according to the Centers for Disease Control and Prevention.

Coccidioides is also on the WHO list., a fungus that causes an infection called valley fever. Historically found in the southwestern United States, scientists have predicted that its range could expand 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 mushrooms 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 fungus after harvest. In the same way that doctors use antifungals to treat fungal infections in humans, farmers use fungicides, a type of pesticide, to kill fungal diseases that invade crops.

But essential fungicides can make essential antifungal medications useless.

Indeed, many fungicides have the same molecular target as antifungal drugs, including existing drugs, as well as some highly anticipated new ones that are in the late 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 grow in soil and decaying plant matter), it may develop resistance. If these mutated fungi then infect humans, they already have the ability to evade the antifungal that targets them.

The above scenario is not hypothetical. Scientists have linked commonly used fungicides to increasingly drug-resistant infections of a fungus called Aspergillus fumigatus in 40 countries, including the United States.

Of particular concern is that the fungus has developed resistance to an entire class of antifungals called azoles, the type of medication most commonly 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.

“We’re down to three classes of antifungals, and one of them is the azoles,” said Norman Van Rhijn, a researcher at the Manchester Fungal Infection Group at the University of Manchester in the United Kingdom.

Several new drugs are also in play, including 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 present this as a conflict between medicine and agriculture,” said Leah Cowen, a professor of molecular genetics at the University of Toronto. “It’s not that we need antifungals for one or the other, we need both. but with different targets.

A need for new antifungals

Humans are much more closely related to fungi than to bacteria and viruses: we share about half of our DNA with fungi, and many proteins essential for fungal survival 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 causing serious damage to a human cell. That’s why many antifungals have serious side effects, Van Rhijn said.

Additionally, fungi can develop resistance to a drug very quickly.

Like viruses and bacteria, they have the innate ability to reproduce quickly and mutate, and these mutations can lead to strains that render drugs ineffective.

This also happens 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 antifungal drugs to treat invasive infections, compared to several dozen classes of antibacterials,” Cowen said.

Those that are available are far from perfect, she added. “Some are toxic, others are susceptible to resistance, and some have a limited spectrum of activity.”

Anna Selmecki, associate professor of microbiology and immunology at the University of Minnesota Medical School, was emphatic about the urgent need for more drugs that can effectively combat fungus.

“I worry that many patients will die because our current range of antifungal medications is limited and more fungi are resistant to the few antifungal medications available,” Selmecki said.

Competing targets

It takes about 25 years to develop a new antifungal drug, and an equally 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 these are often the same targets used in both antifungal drugs and fungicides.

In the case of the new drug olorofim, it is a fungicide called ipflufenoquine, used on fruit and nut trees and in vineyards. The Environmental Protection Agency, which reviews and approves pesticides independently of the FDA, approved ipflufenoquine as a fungicide nearly two years ago.

Since the FDA requested more data on olorofim from British drugmaker F2G, Inc., the new antifungal is in phase 3 clinical trials. Studies so far have shown the drug is effective against the fungus that causes valley fever, as well as a rare emerging fungal infection called lomentosporiosis, which is associated with organ transplants.

“Olorofim is probably the most promising antifungal,” said Dallas Smith, an epidemiologist in the CDC’s mycotic diseases branch, noting that the drug has been shown to be effective against “almost all fungal infections.”

Both treatments target the same target: an enzyme called dihydroorotate dehydrogenase.

According to Van Rhijn, other antifungal drugs are in the pipeline and are following the same trajectory as olorofim. He fears that a new antifungal called fosmanogepix, which has not yet been approved by the FDA, could be threatened by a pesticide called aminopyrifen – effective against a type of fungus that invades soft fruits like strawberries – which acts on the same target.

Cowen agreed.

“The same story repeats itself,” she said.

Can interagency cooperation save antifungals?

Competition with fungicides is not the only problem causing resistance to antifungal drugs. Poor diagnostic testing, limited surveillance of infections and drug abuse (fungal infections are often misdiagnosed) also play a role, but more coordinated surveillance of new drugs and pesticides and their targets will play an important role in preserving the effectiveness of antifungals. move forward. This means that regulatory agencies like the FDA and 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 in this area,” Smith said.

With careful planning, there will be room for olorofim and ipflufenoquine, as well as other antifungals and fungicides with the same targets, he said. “We know that not all infections will be inherently resistant to older antifungal drugs. »

In September, the EPA announced that it was working with the Department of Health and Human Services and the Department of Agriculture on a potential framework that would better protect antifungals. The agency hopes to finalize the framework by the end of this year, Remmington Belford, EPA press secretary, told NBC News in an emailed statement.

Once finalized, the framework will provide guidance for collaboration between agencies that deal with human health and the EPA, which approves pesticides, and on how pesticides can be evaluated for any potential resistance threats. to the antimicrobials they may pose.

Cowen said that even without such a framework, potentially life-saving antifungals should not be abandoned because of the risks new fungicides pose to their effectiveness.

“We still desperately need this new class of antifungals. Olorofim has great potential to treat fungal infections for which we currently have no treatment,” she said.

This article was originally published on NBCNews.com

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