Revealing Fundamental Mechanisms By Which Fungi Deadly to Humans Survive Antifungal Treatment

The Science

The fungal pathogen Aspergillus fumigatus is responsible for approximately 100,000 human deaths annually. Cell-wall-targeting antifungal drugs called echinocandins have been developed, and while they work well for Candida species, they have shown limited efficacy against A. fumigatus. A recent multi-institutional study successfully identified the mechanism behind this pathogen’s survival against antifungal drugs. On a molecular level, this fungus reshuffles its biosynthesis of carbohydrate polymers to rebuild its cell walls—the armor covering the surface of the fungal cell for protection.. This new molecular-level information on carbohydrate restructuring and assembly by this pathogenic fungus gives researchers important fundamental insight that can be used in developing antifungal drugs.

The Impact

Life-threatening invasive fungal infections afflict more than 2 million individuals annually, with high mortality rates even after patients received intensive treatment. Aspergillus fumigatus is among the most deadly fungal species. Infections by these fungi have become even more severe amid a post-COVID world. This study identified the reason behind therapeutic failures by understanding how this pathogenic fungus rebuilds its carbohydrate armor for survival. These new findings provide the structural foundation to guide scientists to design next-generation antifungal drugs with improved efficacy.

Summary

Antifungal drugs called echinocandins inhibit the biosynthesis of β-1,3-glucan, an essential polysaccharide component of the fungal cell wall. However, the efficacy of echinocandins against the prevalent and deadly fungal pathogen Aspergillus fumigatus has been shown to be limited. In this study, solid-state nuclear magnetic resonance (NMR), molecular dynamics modeling, and other techniques were used to show that echinocandins induce dynamic changes in the assembly of polymers within the Aspergillus fumigatus cell wall. The reduction of β-1,3-glucan induced by echinocandins was found to be accompanied by a concurrent increase in levels of other polysaccharides, such as chitin, chitosan, and α-1,3-glucans. These other polysaccharides have a physical association with chitin, and this association maintains cell wall integrity and modulates water permeability. The rearrangement of this macromolecular network controls the permeability and circulation of the drug through the cell wall. Thus, these results show how echinocandin treatment triggers compensatory rearrangements in the cell wall that may help Aspergillus fumigatus tolerate the drugs’ antifungal effect. The Environmental Molecular Sciences Laboratory, a Department of Energy (DOE) Office of Science user facility, contributed assistance in NMR spectroscopy and the access to high-field NMR instruments, allowing for cross-comparison of the effects from three different drugs within the echinocandin family, which was essential to the success of the project. 

Contacts

Andrew S. Lipton, EMSL | Pacific Northwest National Laboratory, as.lipton@pnnl.gov

Tuo Wang, Michigan State University, wangtuo1@msu.edu

Funding

This work was primarily supported by a grant from the National Institutes of Health. A portion of the research was supported by a Large-Scale Research award from the Environmental Molecular Sciences Laboratory, a DOE Office of Science user facility sponsored by the Biological and Environmental Research program. Additional support was provided by the National Science Foundation, the state of Florida, and the DOE Office of Basic Energy Sciences.

Publication

M.C. Dickwella Widanage, et al. “Adaptative survival of Aspergillus fumigatus to echinocandins arises from cell wall remodeling beyond β-1,3-glucan synthesis inhibition.” Nature Communications 15, 6382 (2024). [DOI: 10.1038/s41467-024-50799-8]