Adaptative survival of Aspergillus fumigatus to echinocandins arises from cell wall remodeling beyond β-1,3-glucan synthesis inhibition

Antifungal echinocandins inhibit the biosynthesis of beta-1,3-glucan, a major and essential polysaccharide component of the fungal cell wall. However, the efficacy of echinocandins against the pathogen Aspergillus fumigatus is limited. Here, we use solid-state nuclear magnetic resonance (ssNMR) and other techniques to show that echinocandins induce dynamic changes in the assembly of mobile and rigid polymers within the A. fumigatus cell wall. The reduction of beta-1,3-glucan induced by echinocandins is accompanied by a concurrent increase in levels of chitin, chitosan, and highly polymorphic alpha-1,3-glucans, whose physical association with chitin maintains cell wall integrity and modulates water permeability. The rearrangement of the macromolecular network is dynamic and controls the permeability and circulation of the drug throughout the cell wall. Thus, our results indicate that echinocandin treatment triggers compensatory rearrangements in the cell wall that may help A. fumigatus to tolerate the drugs' antifungal effects. Echinocandins inhibit the biosynthesis of beta-1,3-glucan, an essential component of the fungal cell wall, but their efficacy against the pathogen Aspergillus fumigatus is limited. Here, Dickwella Widanage et al. show that A. fumigatus responds to echinocandin treatment by remodelling various cell wall polymers, thus maintaining cell wall integrity and modulating the permeability and circulation of the drug in the cell wall.