Two EPIC research groups target ways to fight brain-eating amoebas

One research group at the Clemson University Eukaryotic Pathogens Innovation Center has identified a compound that inhibits a key enzyme that brain-eating amoebas need to live, while a second laboratory is working on a more efficient and effective way to get that compound into the brain.

Naegleria fowleri thrives in warm freshwater lakes, ponds and rivers.

While infection is rare, if water containing the amoeba is forced up a person's nose while swimming or diving, the amoeba can travel to the brain, causing primary amoebic meningoencephalitis, an infection that results in tissue damage and hemorrhagic necrosis. It is nearly always fatal - only four of the 157 people with confirmed cases in the United States from 1962 through 2022 survived.

Researchers in James Morris' lab have identified a compound that inhibits a key enzyme that extends the life in animals infected with brain-eating amoeba.

Blocking a critical pathway

Researchers in James Morris' lab discovered that inhibitors of sugar metabolism designed to treat brain cancer are toxic to N. fowleri.

Jillian McKeon, a postdoctoral fellow in the lab, read a 2020 scientific paper from the University of Texas MD Anderson Cancer Center about a compound, HEX, that blocked a critical metabolic pathway in certain types of brain cancer cells.

HEX blocked enolase, an essential enzyme involved in glycolysis, which is a series of reactions that extract energy from glucose and is necessary for cell growth.

Coincidentally, the Morris lab had tested the same compound on trypanosomes, a group of parasites that cause African sleeping sickness, years before at the request of Florian Muller, the MD Anderson researcher.

More potent

When Morris' lab tested HEX against N. fowleri grown in the lab, it was more potent against the amoeba than it was the brain tumor.

When researchers tested HEX in an animal model by delivering the compound intranasally, they found that it extended the life of infected rats compared to rodents that did not receive the compound, but it did not kill all the amoeba.

"The experiments weren't exhaustive. We didn't try every dose. We didn't try combinations with other drugs. But what we showed was that when you put the compound up their noses, it meaningfully extended their lives," Morris said.

Morris said he thinks that it didn't kill all of the amoeba because they couldn't keep the level of HEX high enough for long enough.

Jessica Larsen's research focuses on drug delivery, biomaterials and nanotechnology.

Hijacking the amoeba's route

That's where Jessica Larsen's research comes in.

Larsen, who is the Carol and John Cromer '63 Family Endowed Associate Professor in Clemson's Department of Chemical and Biomolecular Engineering and a researcher at EPIC, focuses on drug delivery, biomaterials and nanotechnology.

Larsen encapsulated the HEX molecule into a nanoparticle made of polymers, called polymersomes, that can help deliver drugs to the brain. Morris' lab has proven the polymersome encapsulated HEX kills the brain-eating amoeba in culture.

Now, the challenge is getting enough of the drug to the brain when it is administered intranasally.

"The brain-eating amoeba gets into the brain through the nose, so we're looking to hijack that route for therapy," she said.

Larsen's group is researching two ways to administer the drug - through intranasal drops which would have to be administered through repeated single doses and through nebulization so it could be administered continuously through a face mask.

"We're working on figuring out where these polymersomes go when we nebulize them and give them to a mouse. We're trying to maximize how much ends up in the brain," she said.

Finding the optimal size

Larsen said usually less than 1% of the sprayed dose of most intranasal therapeutics gets to the brain.

"When you're using a liquid droplet, it's hard to get a lot of it to the brain. That's why we're trying to control these aerosolized droplets. There's an optimum size of an aerosol droplet to promote deposition in the nose instead of being breathed out or being taken up by the immune system," she said. "So, we're trying to figure out how to get that optimized droplet size so that we can truly maximize how much of this gets to the brain."

Larsen said polymersomes can be used to deliver drugs to treat other diseases.

"We really have a plug-and-play system where I can take different polymer pieces and put them together to create a tunable release system based on various characteristics, such as those that degrade in response to high enzyme activity or to different temperatures and pH levels. We have polymers that degrade in response to radiation or reactive oxygen species. This allows the polymersome to degrade in response to specific diseases," she said.

Larsen hopes the brain-eating amoeba research eventually opens a new avenue of easy at-home or out-of-hospital administration for neural therapeutics.

Detailed findings for the research involving the Morris lab were published in the journal PLOS Pathogens in an article titled "Enolase inhibitors as therapeutic leads for Naegleria fowleri infection."

Public link

Please use the above public link if you want to share this noodl on another website.