Identification of the antiphagocytic trypacidin gene cluster in the human-pathogenic fungus Aspergillus fumigatus.
The opportunistic human pathogen Aspergillus fumigatus produces numerous different natural products. The genetic basis for the biosynthesis of a number of known metabolites has remained unknown. The gene cluster encoding for the biosynthesis of the conidia-bound metabolite trypacidin is of particular interest because of its antiprotozoal activity and possible role in the infection process. Here, we show that the genes encoding the biosynthesis enzymes of trypacidin reside within an orphan gene cluster in A. fumigatus. Genome mining identified tynC as an uncharacterized polyketide synthase with high similarity to known enzymes, whose products are structurally related to trypacidin including endocrocin and fumicycline. Gene deletion of tynC resulted in the complete absence of trypacidin production, which was fully restored when the mutant strain was complemented with the wild-type gene. When confronted with macrophages, the tynC deletion mutant conidia were more frequently phagocytosed than those of the parental wild-type strain. This was also found for phagocytic amoebae of the species Dictyostelium discoideum, which showed increased phagocytosis of ΔtynC conidia. Both macrophages and amoebae were also sensitive to trypacidin. Therefore, our results suggest that the conidium-bound trypacidin could have a protective function against phagocytes both in the environment and during the infection process.
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Beutenbergstrasse 11a, 07745, Jena, Germany.|Friedrich Schiller University Jena, Jena, Germany.
Derek J
DJ
Mattern
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Beutenbergstrasse 11a, 07745, Jena, Germany.|Friedrich Schiller University Jena, Jena, Germany.
Hanno
H
Schoeler
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Beutenbergstrasse 11a, 07745, Jena, Germany.|Friedrich Schiller University Jena, Jena, Germany.
Jakob
J
Weber
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Beutenbergstrasse 11a, 07745, Jena, Germany.|Friedrich Schiller University Jena, Jena, Germany.
Silvia
S
Novohradská
Friedrich Schiller University Jena, Jena, Germany.|Department of Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
Kaswara
K
Kraibooj
Department of Infection Biology, Leibniz Institute for Infection Biology and Natural Product Research (HKI), Jena, Germany.
Hans-Martin
HM
Dahse
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Beutenbergstrasse 11a, 07745, Jena, Germany.
Falk
F
Hillmann
Leibniz Junior Research Group - Biobricks of Microbial Natural Product Syntheses, Jena, Germany.
Vito
V
Valiante
Friedrich Schiller University Jena, Jena, Germany.|Department of Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
Marc Thilo
MT
Figge
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Beutenbergstrasse 11a, 07745, Jena, Germany. axel.brakhage@hki-jena.de.|Friedrich Schiller University Jena, Jena, Germany. axel.brakhage@hki-jena.de.
Axel A
AA
Brakhage
D000818:Animals; D001232:Aspergillus fumigatus / Q000235:genetics* / Q000378:metabolism*; D001688:Biological Products / Q000378:metabolism*; D002478:Cells, Cultured; D004023:Dictyostelium / Q000187:drug effects / Q000502:physiology; D017353:Gene Deletion; D005816:Genetic Complementation Test; D007155:Immunologic Factors / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D005810:Multigene Family; D010587:Phagocytosis / Q000187:drug effects*
D001688:Biological Products; D007155:Immunologic Factors
Aspergillus fumigatus; Dictyostelium discoideum; Genome mining; Macrophage; Polyketide; Trypacidin