New research from the Hoskins Lab in the Department of Biochemistry and the Hull Lab in the Department of Biomolecular Chemistry points to a promising new avenue for treating harmful fungal infections.
In 2022, the researchers received the Badger Challenge Award to explore possible treatments for fungal infections. Most pathogenic fungal spores are benign to most healthy people with strong immune systems. In immunocompromised people, however, fungal infections can result in serious illness, which has been documented to lead to death in about seventy percent of cases.
The team sought to improve treatment by reducing the need for current antifungal medications — which can pose toxicity to humans — through inhibition of fungal pre-mRNA splicing (an essential step for gene expression).
Their latest findings, published in the American Society for Microbiology’s mSphere, indicate that inhibiting pre-mRNA splicing is a promising direction for future antifungal research.
The research was led by Sierra Love and Megan McKeon, former genetics graduate students in the Hoskins and Hull Labs, respectively. They examined how PladB, a molecule used to inhibit pre-mRNA splicing in human cells, impacts splicing in Cryptococcus neoformans, a fungal pathogen.
Their experiments showed that PladB was effective at reducing C. neoformans growth and germination, and that it was more effective when used in combination with other drugs.
“This is a really cool proof of principle for developing antifungal therapeutics,” says McKeon, who will soon start a position as a scientist at Arrowhead Pharmaceuticals. “We hope that in the future, we can use combinations of drugs, including splicing inhibitors, to target cells in specific ways, without overwhelming patients’ bodies with potentially toxic medication.”
The scientists aren’t sure why the combination of antifungal medication and splicing inhibitors was so effective. Love, now a scientist at ThermoFisher Scientific, theorizes that the antifungal medications they chose compromised cell wall integrity. “[The medications] could allow the splicing inhibitors to more easily get into the cell or and stay there, rather than getting pumped right back out.”
“The work so far has shown that pathogenic fungi are sensitive to [pre-mRNA] splicing inhibitors during growth and germination,” says biochemistry professor Aaron Hoskins. “The challenge now is to see if fungal-specific inhibitors can be designed to inhibit splicing in these pathogens but not [inhibit] the human splicing machinery.”
Written by Renata Solan.