PNNL

Abstract

The insufficient efficacy of existing antifungal drugs and the rise in resistance necessitate the development of new therapeutic agents with novel functional mechanisms1,2. Echinocandins are an important class of antifungals that inhibit ß-1,3-glucan biosynthesis to interfere with cell wall structure and function3,4. Although ß-1,3-glucan biosynthesis is essential for fungal viability, the efficacy of echinocandins is constrained both in vivo and in vitro, which may arise from alterations in the overall cell wall structure, a facet that remains inadequately understood. Using solid-state nuclear magnetic resonance (ssNMR), this present study shows how echinocandins entirely remodel the supramolecular assembly of the cell wall in the human pathogenic fungus Aspergillus fumigatus. The reduction of ß-1,3-glucan and the concurrent rise in chitin levels unexpectedly coincide with the emergence of chitosan and an increase in highly polymorphic a-1,3-glucans, whose physical association with chitin maintained the wall integrity and modulated cell wall mobility and water-permeability. Precisely identifying these compensatory reactions occurring in the cell wall during echinocandin treatment is crucial for understanding how fungi can counteract the antifungal effects of drugs targeting essential cell wall polysaccharides and may suggest new strategies for improving the efficacy of cell wall inhibitors.