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

Malitha C. Dickwella Widanage, Isha Gautam, Daipayan Sarkar, Frederic Mentink-Vigier, Josh V. Vermaas, Shi-You Ding, Andrew S. Lipton, Thierry Fontaine, Jean-Paul Latgé, Ping Wang and Tuo Wang ()
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Malitha C. Dickwella Widanage: Michigan State University
Isha Gautam: Michigan State University
Daipayan Sarkar: MSU-DOE Plant Research Laboratory
Frederic Mentink-Vigier: National High Magnetic Field Laboratory
Josh V. Vermaas: MSU-DOE Plant Research Laboratory
Shi-You Ding: Michigan State University
Andrew S. Lipton: Pacific Northwest National Laboratory
Thierry Fontaine: F-
Jean-Paul Latgé: University of Crete
Ping Wang: Louisiana State University Health Sciences Center
Tuo Wang: Michigan State University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50799-8

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