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SHR Neuro Cancer Cardio Lipid Metab Microb

Dichtl, K; Samantaray, S; Aimanianda, V; Zhu, Z; Prévost, MC; Latgé, JP; Ebel, F; Wagener, J.
Aspergillus fumigatus devoid of cell wall β-1,3-glucan is viable, massively sheds galactomannan and is killed by septum formation inhibitors.
Mol Microbiol. 2015; 95(3): 458-71. Doi: 10.1111/mmi.12877
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Leading authors Med Uni Graz: Dichtl Karl
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Abstract:: Echinocandins inhibit β-1,3-glucan synthesis and are one of the few antimycotic drug classes effective against Aspergillus spp. In this study, we characterized the β-1,3-glucan synthase Fks1 of Aspergillus fumigatus, the putative target of echinocandins. Data obtained with a conditional mutant suggest that fks1 is not essential. In agreement, we successfully constructed a viable Δfks1 deletion mutant. Lack of Fks1 results in characteristic growth phenotypes similar to wild type treated with echinocandins and an increased susceptibility to calcofluor white and sodium dodecyl sulfate. In agreement with Fks1 being the only β-1,3-glucan synthase in A. fumigatus, the cell wall is devoid of β-1,3-glucan. This is accompanied by a compensatory increase of chitin and galactosaminogalactan and a significant decrease in cell wall galactomannan due to a massively enhanced galactomannan shedding. Our data furthermore suggest that inhibition of hyphal septation can overcome the limitations of echinocandin therapy. Compounds inhibiting septum formation boosted the antifungal activity of caspofungin. Thus, development of clinically applicable inhibitors of septum formation is a promising strategy to improve existing antifungal therapy.
Find related publications in this database (using NLM MeSH Indexing): Antifungal Agents - pharmacology; Aspergillosis - drug therapy; Aspergillus fumigatus - cytology, drug effects, genetics, metabolism; Benzenesulfonates - pharmacology; Caspofungin - administration & dosage; Cell Wall - metabolism; Chitin - metabolism; Echinocandins - pharmacology; Galactose - analogs & derivatives; Glucosyltransferases - genetics, metabolism; Hyphae - drug effects; Lipopeptides - administration & dosage; Mannans - metabolism; Mutation - administration & dosage; Phenotype - administration & dosage; Polysaccharides - metabolism; beta-Glucans - analysis