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

• Published in: Nature communications Vol. 15; no. 1; pp. 6382 - 13
• Main Authors: Dickwella Widanage, Malitha C., Gautam, Isha, Sarkar, Daipayan, Mentink-Vigier, Frederic, Vermaas, Josh V., Ding, Shi-You, Lipton, Andrew S., Fontaine, Thierry, Latgé, Jean-Paul, Wang, Ping, Wang, Tuo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-07-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/6; 140/131; 147/143; 147/3; 631/326/193/2538; 631/326/22/1292; 631/326/22/1434; 631/45/535/878/1264; 639/638/45/72/1205; Antifungal Agents - pharmacology; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - metabolism; beta-Glucans - metabolism; Biosynthesis; Cell Wall - drug effects; Cell Wall - metabolism; Cell walls; Chitin; Chitin - metabolism; Chitosan; Chitosan - pharmacology; Echinocandins; Echinocandins - pharmacology; Effectiveness; Fungi; Fungicides; Glucan; Glucans; Glucans - biosynthesis; Glucans - metabolism; Humanities and Social Sciences; Integrity; Life Sciences; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; multidisciplinary; NMR; Nuclear magnetic resonance; Pathogens; Permeability; Polymers; Polysaccharides; Science; Science & Technology - Other Topics; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50799-8

Antifungal echinocandins inhibit the biosynthesis of β−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 β−1,3-glucan induced by echinocandins is accompanied by a concurrent increase in levels of chitin, chitosan, and highly polymorphic α−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 β−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.