Contributors: Michigan State University East Lansing; Michigan State University System; National High Magnetic Field Laboratory (NHMFL); Florida State University Tallahassee (FSU); Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF); Institut Pasteur Paris (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Pacific Northwest National Laboratory (PNNL); University of Crete Heraklion (UOC); Louisiana State University (LSU); This work was primarily supported by the National Institutes of Health (NIH) grant AI173270 to T.W. The National High Magnetic Field Laboratory is supported by the National Science Foundation through NSF/DMR-1644779 and 2128556, and the State of Florida. The MAS-DNP system at NHMFL is funded in part by NIH S10 OD018519, P41 GM122698, and RM1 GM148766. The modeling work was supported in part through computational resources and services provided by the Institute for Cyber-Enabled Research at Michigan State University. D.S. and J.V.V. acknowledge support from DE-FG02-91ER20021 from the U.S. Department of Energy, Office of Basic Energy Sciences. J.V.V. additionally acknowledges NIH under Award Number R35GM155317. S.-Y. D. acknowledge the support from the U.S. Department of Energy, Office of Science, Biological and Environmental Research Program, under award number DE-SC0019072, and U.S. National Science Foundation under award number 2321398. The 850 MHz NMR spectra were collected on project award 51907 (DOI:10.46936/lser.proj.2021.51907/60000363) from the Environmental Molecular Sciences Laboratory, a DOE Office of Science User Facility sponsored by the Biological and Environmental Research program under Contract No. DE-AC05-76RL01830.
Abstract: International audience ; 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.
Processing Request
No Comments.