Structural Remodeling of Fungal Cell Wall Promotes Resistance to Echinocandins

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 {beta}-1,3-glucan biosynthesis to interfere with cell wall structure and function3,4. However, their efficacy is limited by the fungistatic activity against Aspergillus species and the trailing effect during clinical application. Here, we describe how echinocandins remodel the supramolecular assembly of carbohydrate polymers in the fungal cell wall in an unexpected manner, possibly resulting in a subsequent inhibition of the activity of these drugs. Solid-state nuclear magnetic resonance (ssNMR) analysis of intact cells from the human pathogenic fungus Aspergillus fumigatus showed that the loss of {beta}-1,3-glucan and the increase of chitin content led to a decrease in cell wall mobility and water-permeability, thus enhancing resistance to environmental stresses. Chitosan and -1,3-glucan were found to be important buffering molecules whose physical association with chitin maintained the wall integrity. These new findings revealed the difficult-to-understand structural principles governing fungal pathogens response to echinocandins and opened new avenues for designing novel antifungal agents with improved efficacy.