title: Aspergillus fumigatus devoid of cell wall β-1,3-glucan is viable, massively sheds galactomannan and is killed by septum formation inhibitors.
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.
authors.affiliation: Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, 80336, Munich, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Dichtl
authors.forename: Sweta
authors.initials: S
authors.lastname: Samantaray
authors.forename: Vishukumar
authors.initials: V
authors.lastname: Aimanianda
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Zhu
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Prévost
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latgé
authors.forename: Frank
authors.initials: F
authors.lastname: Ebel
authors.forename: Johannes
authors.initials: J
authors.lastname: Wagener
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001557:Benzenesulfonates / Q000494:pharmacology; D000077336:Caspofungin; D002473:Cell Wall / Q000378:metabolism; D002686:Chitin / Q000378:metabolism; D054714:Echinocandins / Q000494:pharmacology*; D005690:Galactose / Q000031:analogs & derivatives; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D025301:Hyphae / Q000187:drug effects; D055666:Lipopeptides; D008351:Mannans / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D011134:Polysaccharides / Q000378:metabolism; D047071:beta-Glucans / Q000032:analysis*
chemical_list: D000935:Antifungal Agents; D001557:Benzenesulfonates; D054714:Echinocandins; D055666:Lipopeptides; D008351:Mannans; D011134:Polysaccharides; D047071:beta-Glucans; C062157:galactosaminogalactan; C012990:galactomannan; D002686:Chitin; C007061:C.I. Fluorescent Brightening Agent 28; C033363:beta-1,3-glucan; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; D000077336:Caspofungin; D005690:Galactose