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 more data. If approved, it would be the first time since the early 2000s that the FDA has approved an antifungal drug that works in an entirely new way.
This could not have come at a more important time. In recent years, the potential danger that fungal infections pose to human health has become increasingly apparent, as fungi evolve to evade treatments and spread beyond typical geographic areas. It’s coming. Doctors around the world are desperate for new medicines to combat this growing threat.
“The problem of fungal diseases has reached the point where the World Health Organization recognizes them as a widespread threat,” says Johns Hopkins Bloomberg School of Public Health microbiologist and professor of molecular microbiology and immunology. said Dr. Arturo Casadeval. Baltimore.
In the second half of 2022, WHO releases first list of priority fungal pathogens — Officials said 19 fungi pose a serious threat to human health. This includes Candida auris, a highly drug-resistant yeast that infects critically ill hospitalized patients. According to , the number of infections in the United States tripled in 2021 alone. 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 predict that its range could extend as far north as the Canadian border and as far east as the Great Plains by the end of the century.
The situation is complicated by the impact of fungi on global food systems.
Fungi thrive in the soil, and fungal diseases have long been a major problem in agriculture. one quarter One of the world’s crops is lost to a fungal disease before it can even be harvested. Another 20% die from fungal infections after harvest. Just as doctors use antifungal drugs to treat fungal infections in humans, farmers use fungicides, a type of insecticide, to kill fungal diseases infesting crops.
But the much-needed fungicide may render important antifungal drugs useless.
That’s because many fungicides, including existing drugs as well as long-awaited new drugs in the final stages of clinical trials, share the same molecular targets as antifungals. Many fungi that can infect humans also thrive in soil and decaying plants, and the fungi can develop resistance to them if they are regularly exposed to fungicides meant to kill them. there is. Even if these mutated fungi were to infect humans, they already have the ability to evade antifungal drugs that target them.
The above scenario is not hypothetical. Scientists have pointed to a link between commonly used fungicides and increased drug resistance in a fungus called Aspergillus fumigatus. in 40 countries including the US
Of particular concern is that the fungus has developed resistance to a whole class of antifungal drugs called azoles, the type most commonly prescribed for fungal infections. In addition to treating a wide range of infections, it is the only antifungal medication that can be taken at home and the only antifungal medication that can be taken for longer than the six months often required to completely cure an infection.
“Antifungal drugs have been narrowed down to three classes, one of which is the azoles,” said Norman van Rijn, a researcher at the Manchester Fungal Infections Group at the University of Manchester in the UK.
Some new drugs are also out of balance, including olorofime, 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 medicine versus agriculture conflict,” says Leah Cowen, a professor of molecular genetics at the University of Toronto. But the targets are different. ”
The need for new antifungal drugs
Humans have a much closer relationship with fungi than with bacteria and viruses. About half Our DNA is closely related to fungi, and many of the proteins essential for fungal survival are also essential for human cells.
Therefore, it is very difficult to find molecular targets within fungal cells that can be attacked without significant damage to human cells, which is why many antifungal drugs come with severe side effects.・Mr. Line said.
Additionally, fungi can rapidly develop resistance to drugs.
Like viruses and bacteria, they have an innate ability to rapidly multiply and mutate, and those mutations can give rise to strains that render the drug ineffective.
This also happens in the world of bacteria and antibiotics. Antibiotic resistance is also a major public health threat. However, there are still many antibiotics for doctors to choose from.
“Compared to dozens of classes of antibiotics, there are only three major classes of antifungals to treat invasive infections,” Cowen said.
She added that what is currently available is far from perfect. “Some are toxic, some are sensitive to tolerance, and some have a limited range of activity.”
Anna Cermekki, associate professor of microbiology and immunology at the University of Minnesota Medical School, spoke candidly about the dire need for additional drugs that can effectively fight fungi.
“Current antifungal drugs have limitations, and as more and more fungi become resistant to the few available antifungal drugs, I worry that many patients will die,” Selmetski said. Ta.
competing targets
It takes about 25 years to develop a new antifungal drug, and it takes an equally long time to develop a new fungicide, Van Rijn said. Scientists have so far identified only a small number of viable molecular targets within fungal cells, but they are often the same targets used in both antifungals and fungicides.
In the case of the new drug olorofim, it is a fungicide called ipflufenoquine. In fruit and nut trees and vineyards. The Environmental Protection Agency, which reviews and approves pesticides independently of the FDA, Ipflufenoquine Almost two years ago as a fungicide.
Since the FDA requested more data on olorofime from British pharmaceutical company F2G, the new antifungal drug Phase 3 clinical trial. Previous research has shown that the drug is effective against not only the fungus that causes Valley fever. Lomentospopolis It has been linked to organ transplants.
“Olorofim is probably the most promising antifungal drug,” said Dallas Smith, an epidemiologist in the CDC’s division of fungal diseases, saying the drug has been shown to be effective against “almost all fungal infections.” He pointed out that there was.
Both treatments target the same enzyme called dihydroorotate dehydrogenase.
Other antifungal drugs following the same trajectory as olorofim are also in the pipeline, Van Rijn said. He said a new antifungal drug called fosmanogepix (not yet FDA approved) could be threatened by an insecticide called aminopyrifene, which is effective against some types of invading fungi. I’m concerned about something. soft fruits Like strawberries, they act on the same targets.
Cowen agreed.
“The same story is unfolding again,” she said.
Can interagency collaboration save on antifungal drugs?
Competition with fungicides is not the only problem promoting antifungal resistance. Inadequate diagnostic testing and little monitoring of infections and drug misuse (fungal infections are often misdiagnosed) have an impact as well, but new drugs and pesticides and their targets need to be better coordinated. Monitoring plays an important role in maintaining the effectiveness of antifungal drugs. We are moving forward. This means that regulatory agencies such as the FDA and EPA need to cooperate when approving new drugs and disinfectants.
“We need to balance antifungal medicines for humans with the world’s food supply, and we need more collaboration to do that,” Smith said.
With careful planning, he said, there could be room for both ololofime and ipflufenoquine, as well as other antifungals and fungicides with the same targets. “We know that not all infections are inherently resistant to older antifungal drugs.”
In September, the EPA announced The company was working with the Departments of Health and Human Services and the Department of Agriculture on a framework that could better protect antifungal drugs. EPA spokesperson Remington Belford told NBC News in an emailed statement that the agency expects to finalize the framework by the end of this year.
Once completed, this framework will provide guidance on collaboration between human health agencies and the EPA, which approves pesticides, and how to evaluate pesticides for the potential threat to antimicrobial resistance they may pose. will be provided.
Cowen said that even without such a framework, potentially life-saving antifungal drugs should not be stopped because of the risks that new fungicides pose to their effectiveness. .
“We still desperately need this new class of antifungal drugs. Olorofim has great potential to treat fungal infections for which there is currently no treatment,” she said.
