Abstract
The high mortality of invasive fungal infections, and the limited number and inefficacy of antifungals necessitate the development of new agents with novel mechanisms and targets. The fungal cell wall is a promising target as it contains polysaccharides absent in humans, however, its molecular structure remains elusive. Here we report the architecture of the cell walls in the pathogenic fungus Aspergillus fumigatus. Solid-state NMR spectroscopy, assisted by dynamic nuclear polarization and glycosyl linkage analysis, reveals that chitin and α-1,3-glucan build a hydrophobic scaffold that is surrounded by a hydrated matrix of diversely linked β-glucans and capped by a dynamic layer of glycoproteins and α-1,3-glucan. The two-domain distribution of α-1,3-glucans signifies the dual functions of this molecule: contributing to cell wall rigidity and fungal virulence. This study provides a high-resolution model of fungal cell walls and serves as the basis for assessing drug response to promote the development of wall-targeted antifungals.
Highlights
The high mortality of invasive fungal infections, and the limited number and inefficacy of antifungals necessitate the development of new agents with novel mechanisms and targets
Since mannan is a major component of fungal glycoproteins purposely forming an outmost layer of fungal cell walls[1,15], our results reveal that this outer shell is highly dynamic and spatially separated from the relatively rigid inner domain of chitin and glucans
Solid-state NMR and magic-angle spinning (MAS)-dynamic nuclear polarization (DNP) results of 65 intermolecular and interallomorph interactions, site-specific hydration, and molecular mobility steadily indicate a two-domain distribution of molecules: glucans and chitins form a relatively rigid and inner portion of cell walls, while mannoproteins and α-1,3-glucan form the extremely mobile outer shell
Summary
The high mortality of invasive fungal infections, and the limited number and inefficacy of antifungals necessitate the development of new agents with novel mechanisms and targets. Recent efforts have been devoted to developing agents that bind to the fungal cell wall since its polysaccharides are absent in human cells[10,11] Echinocandins are such new compounds that disrupt glucan synthesis and perturb cell wall integrity with reduced toxicity[12,13,14]. The current understanding of the spatial packing has been shaped by the evidence from enzymatic digestion, fractional solubilization, and isolation of cell wall components followed by sugar analysis[18,19] These chemical and enzymatic methods, are destructive and often fail to reveal the complicated polymer assembly generated by biosynthesis machinery. The methods presented in this study enable the investigation of complex carbohydrates in intact cells and will allow the direct detection of fungal responses to antifungal agents through in-situ assessment of cell wall structures
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