Every year, about 20,000 cases of Valley fever are reported to the U.S. Centers for Disease Control and Prevention, with an estimated additional 260,000 annual cases going unreported. In 2023, more than half of these cases came from Arizona alone.
The fungal lung infection is associated with a range of pneumonia-like symptoms in humans and animals, and in severe cases, it can lead to lifelong complications requiring extensive antifungal treatments. While these treatments are often effective in quelling symptoms, many fail to eradicate the fungal pathogen and come with grueling side effects like hair loss, dry skin and kidney damage.
But could a better alternative to Valley fever treatment be right around the corner? One laboratory at NAU thinks so.
Working in tandem with the University of Colorado Boulder, a team of about a dozen research assistants, scientists and students from the Department of Biological Sciences and the Pathogen and Microbiome Institute is embarking on a four-year journey to test the efficacy of Valley fever treatments developed by their chemist partners. Supported by National Institutes of Health funding until 2029, the group hopes to emerge with a swift and safe drug that improves on existing antifungal compounds at the project’s end.
Department of Biological Sciences professor Bridget Barker serves as the primary investigator for NAU’s portion of the study and heads experimental design, personnel management and the interpretation of research findings. Being thoroughly engrossed in fungal biology and Valley fever research since 2002, she said her desire to understand the illness stems from her proximity to those impacted by it and a frustration with people conflating its nationwide rarity with insignificance.
“Even though there is a high burden of disease in the Southwest, it’s still considered relatively rare, which makes it difficult to work on something considered not a problem by so many people,” Barker said. “But when you meet and talk to people who have been directly affected by this disease in your own state on a regular basis, it becomes very personal very fast. It’s our challenge, the challenge of our state and the state of California, to really combat this organism.”
The search for a safer treatment
Treating Valley fever usually entails attacking it at its source: the fungi Coccidioides and its airborne spores. But while many existing treatments successfully inhibit fungal growth, they can also cause harm to the host’s healthy cells, resulting in side effects such as nausea, vomiting and abdominal pain.
With the aim of minimizing collateral damage, researchers at NAU and CU Boulder are specifically looking into the antifungal agent ambruticin S as a potential treatment, which biology doctoral student and study participant Frances Faguy says is unique in that it safely targets a signaling pathway in Coccidioides that is not present in human cells.
“The target for an antifungal is a really important aspect of that antifungal’s efficacy,” Faguy said. “Something that has been a huge problem in other antifungals used to treat Coccidioides and similar fungal pathogens really is the toxicity they cause to other parts of the body. They will target molecules in your cells that are just like the molecules they target in fungal cells, but if it has a target that isn’t also in our body, it will be a safer treatment.”
Ambruticin S represents a step in the right direction for minimally harmful Valley fever treatment, Barker said, but she believes there’s still more to be done. In 2024, CU Boulder researchers began developing chemical analogs of ambruticin S in the hopes of finding a potent version with a simplified means of production, and this summer, Barker’s lab will lead the charge in testing the redesigned molecules.
“An issue with the original product is that it is very expensive and not really amenable to manufacturing,” Barker said. “We’re trying to think about how we can make something that is going to be relatively cost-effective to produce and useful in the clinic.”
Barker’s lab has about four different analogs of ambruticin ready for testing and expectations that dozens of others will flood in as the process continues, each one closer to a solution than the last.
The first step of the study, led by Faguy, includes using plate assays to determine if the newly developed compounds can effectively kill Coccidioides outside of a living host. Faguy also will conduct experiments with the Coccidioides genome to see what fungal proteins the ambruticin compounds are interacting with and how long the compounds bind to said proteins.
Once they have an analog or two that are effective in these initial trials, the scientists will give the compounds to mice to confirm that the drugs can be properly absorbed in living hosts and do not present unwanted symptoms of toxicity. Finally, the compounds will be given to mice with Valley fever to see if the compounds can properly treat and resolve the infection.
Saving lives in the Southwest
Developing a widespread and reliable Valley fever drug will require intensive investigations and evaluations that extend far beyond the scope of this study, but even in the face of a long-lasting drug development journey, Barker said she’s hopeful the lives changed by her team’s results will prove the work was worth it.
“We need to do better,” she said. “We need to have better antifungal drugs to target the fungus specifically, without having these severe side effects in humans. There’s a lot of work that will be going into actually developing this compound, but based on the fact that the raw compound has been shown to be really effective, we have a lot of confidence that at the end of this grant, we’ll have at least a few potential antifungal drugs that can then go on to preclinical trials.”