Fungal infections are common but are often difficult to treat. There are very few antifungal drugs, and the newest one is over 20 years old. One reason for this situation is the fact that most drugs that have antifungal activity are also very toxic to humans.
In a recently published study, researchers led by Damian Krysan, MD, PhD, University of Iowa professor of pediatrics, have identified a highly selective antifungal compound that could pave the way for safer, more effective treatments against life-threatening fungal infections.
“The molecules we found inhibit the fungal enzyme but not the human enzyme. This is exactly the type of drugs that are needed,” says Krysan, who also is a professor of molecular physiology and biophysics, and director of the Division of Pediatric Infectious Disease in the UI Health Care Stead Family Children’s Hospital.
The findings, published in Nature Communications, highlight a novel approach to targeting Cryptococcus neoformans, a fungal pathogen responsible for meningitis in immunocompromised individuals. The paper was selected to be featured on the Editor’s Highlights page, a curated collection of top papers chosen by the journal’s editors.
New drug precisely targets fungal metabolism
Krysan and his colleagues used chemical-genetic screening to discover an isoxazole-based molecule that inhibits acetyl-CoA synthetase (Acs1) — a metabolic enzyme essential for fungal survival under host-like conditions. Structural biology techniques, including X-ray crystallography, allowed the team to create 3D images revealing exactly where the drug binds to the fungal enzyme. This information should help researchers design even better drugs to specifically interact with target enzymes.
The isoxazole compound also shows promise in combination therapies, enhancing the efficacy of existing antifungal drugs like fluconazole.
Discovery may also help drug design for cancer and metabolic disease
Acetyl-CoA synthetase enzymes (Acs) have started to gain interest as potential drug targets for the treatment of cancer and metabolic diseases as well as fungal and parasitic infections. Although a variety of small molecules that inhibit Acs enzymes have been discovered, systematic optimization of these molecules for therapeutic purposes has been challenging due to a lack of structural information to explain how they work.
The discovery of the isoxazole Acs inhibitors and the structural and biochemical characterization of how these drugs inhibit Acs provides new insights that could inform the design of new Acs inhibitors for both infectious diseases as well as the treatment of human cancers and metabolic diseases.
The research was supported by funding from the National Institutes of Health and National Science Foundation, with advanced structural studies conducted at the NYX beamline of the National Synchrotron Light Source II, a U.S. Department of Energy Office of Science user facility.