Last summer, the Food and Drug Administration rejected an application for a new antifungal drug called olorofim and sent it back to the company with a request for more information. If approved, it would be the first time since the early 2000s that the FDA cleared an antifungal drug that works in a completely new way.
It couldn’t come at a more important time: In recent years, the potential threat of fungal infections to human health has become increasingly apparent, as fungi also evolves to avoid treatments or spread beyond their typical geographic regions. Doctors all over the world are eager for new drugs to fight the growing threat.
Dr. Johns Hopkins Bloomberg School of Public Health microbiologist and head of the Department of Molecular Microbiology and Immunology. “The problem with fungal diseases has reached the point where the World Health Organization has recognized it as a widespread threat,” said Arturo Casadeval. Baltimore.
In late 2022 WHO published the first list of priority fungal pathogens — According to the agency, 19 fungi pose a serious threat to human health. It includes highly drug resistant yeast Candida auris, infecting critically ill hospital patients; In 2021 alone, the number of infections in the United States tripled Centers for Disease Control and Prevention.
Also on the WHO list are coccidioids, a fungus that causes an infection called Valley fever. Historically found in the southwestern United States, 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 fungi can have on the global food system.
Fungi thrive in soil, and fungal diseases have long been a major problem in agriculture. one quarter the world’s crops are lost to fungal diseases before harvest. Another 20% succumb to post-harvest fungi. Just as doctors use antifungal drugs to treat fungal infections in humans, farmers use fungicides, a type of pesticide, to kill fungal diseases that overtake plants.
But much-needed fungicides can render critical antifungal drugs useless.
This is because many fungicides share the same molecular target as antifungals, including existing drugs as well as some long-awaited new ones in the final stages of clinical trials. If a fungus is regularly exposed to fungicides designed 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 is not hypothetical. Scientists are increasingly linking commonly used fungicides Drug-resistant infections of the fungus 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 drug most commonly prescribed for fungal infections. In addition to treating a wide range of infections, it is 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 completely clear the infection.
“We fall into three groups of antifungals, and one of them is the azoles,” said Norman Van Rhijn, a researcher in the Manchester Fungal Infections Group at the University of Manchester in the UK.
Several new drugs hang in the balance, including olorofim, which is part of a class of new drugs that has been shown to be effective against azole-resistant Aspergillus.
“We don’t want to paint this as a medicine versus agriculture conflict,” said Leah Cowen, a professor of molecular genetics at the University of Toronto. but with different goals.”
The need for new antifungals
Humans are more closely related to fungi than to bacteria and viruses: We share about half with fungi, our DNA 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 the human cell, which is why many antifungal drugs have serious side effects, Van Rhijn said.
Moreover, fungi can become resistant to the drug very quickly.
Like viruses and bacteria, they can multiply and mutate quickly, and these mutations can lead to strains that make drugs ineffective.
This is also happening in the world of bacteria and antibiotics – Antibiotic resistance is another major threat to public health – but doctors still have more antibiotics to choose from.
“We have only three major antifungal drug classes to treat invasive infections, compared to several dozen antibacterial classes,” Cowen said.
The existing ones are not perfect as they are, he added. “Some are toxic, some are susceptible to resistance, and some have a limited spectrum of activity.”
Anna Selmecki, assistant professor of microbiology and immunology at the Medical School of Minnesota, spoke openly about the great need for more drugs that can effectively fight fungi.
“I `m very anxious patients will die Because our current set of antifungal drugs is limited and most fungi are resistant to the few antifungal drugs available,” said Selmecki.
Competing goals
Van Rhijn said it takes about 25 years to develop a new antifungal drug, and a similarly long time to develop a new fungicide. Scientists have so far identified only a few viable molecular targets in fungal cells, and they are often the same targets used in both antifungal drugs and fungicides.
In the case of the new drug olorophym, it is a fungicide called ipflufenoquin – used. in fruit and nut trees and vineyards. The Environmental Protection Agency, which reviews and approves pesticides independently of the FDA ipflufenogine as a fungicide about two years ago.
As the FDA requested more information from British drugmaker F2G, Inc. about olorofim, a new antifungal phase 3 clinical trials. Research so far has shown that the drug is effective against the causative fungus Valley feveralso called a rare fungal infection lomentosporiosis It is associated with organ transplantation.
“Olorofim is probably the most promising antifungal,” said Dallas Smith, an epidemiologist with the CDC’s Division of Mycotic Diseases, and has shown that the drug is effective against “virtually every 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 follow the same trajectory as Olorofim. He worries that a new antifungal drug called fosmanogepix, which has not yet been approved by the FDA, could be threatened by a pesticide called aminopyrifen. soft fruit like strawberries – works on the same target.
Cowen agreed.
“It’s the same story playing out again,” he said.
Can interagency collaboration save antifungals?
Competition with fungicides is not the only problem with antifungal drug resistance. Poor diagnostic tests, poor infection control and drug abuse – Fungal infections are often misdiagnosed — all play a role, but more coordinated control over new drugs and pesticides and their targets will be critical to maintaining the effectiveness of antifungals moving forward. This means that regulatory agencies such as the FDA and EPA will have to work together when approving new drugs and fungicides.
“We need to balance the global food supply with human antifungals, and we need more collaboration to do that,” Smith said.
With careful planning, there will be room for both olorophym and ipflufenogine, as well as other antifungal agents and fungicides with similar targets, he said. “We know that not all infections will be naturally resistant to older antifungal drugs.”
EPA in September announced he 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 expects to finalize the framework by the end of this year, EPA spokesman Remmington Belford told NBC News in an email.
When complete, the framework will provide guidance for collaboration between human health agencies and the EPA, which approves pesticides, and how pesticides can be assessed for potential threats to antimicrobial resistance.
Even without such a framework, potentially life-saving antifungals should not be discarded because of the risks new fungicides pose to antifungal efficacy, Cowen said.
“We still have a great need for this new class of antifungals. “Olorofim” has great potential to treat fungal infections that currently have no treatment.”