title: Among developmental regulators, StuA but not BrlA is essential for penicillin V production in Penicillium chrysogenum.
abstract: In filamentous fungi, secondary metabolism is often linked with developmental processes such as conidiation. In this study we analyzed the link between secondary metabolism and conidiation in the main industrial producer of the β-lactam antibiotic penicillin, the ascomycete Penicillium chrysogenum. Therefore, we generated mutants defective in two central regulators of conidiation, the transcription factors BrlA and StuA. Inactivation of either brlA or stuA blocked conidiation and altered hyphal morphology during growth on solid media, as shown by light and scanning electron microscopy, but did not affect biomass production during liquid-submerged growth. Genome-wide transcriptional profiling identified a complex StuA- and BrlA-dependent regulatory network, including genes previously shown to be involved in development and secondary metabolism. Remarkably, inactivation of stuA, but not brlA, drastically downregulated expression of the penicillin biosynthetic gene cluster during solid and liquid-submerged growth. In agreement, penicillin V production was wild-type-like in brlA-deficient strains but 99% decreased in stuA-deficient strains during liquid-submerged growth, as shown by high-performance liquid chromatography (HPLC) analysis. Thus, among identified regulators of penicillin V production StuA has the most severe influence. Overexpression of stuA increased the transcript levels of brlA and abaA (another developmental regulator) and derepressed conidiation during liquid-submerged growth but did not affect penicillin V productivity. Taken together, these data demonstrate an intimate but not exclusive link between regulation of development and secondary metabolism in P. chrysogenum.
authors.affiliation: Anti Infectives Microbiology, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sigl
authors.forename: Hubertus
authors.initials: H
authors.lastname: Haas
authors.forename: Thomas
authors.initials: T
authors.lastname: Specht
authors.forename: Kristian
authors.initials: K
authors.lastname: Pfaller
authors.forename: Hubert
authors.initials: H
authors.lastname: Kürnsteiner
authors.forename: Ivo
authors.initials: I
authors.lastname: Zadra
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D025301:Hyphae / Q000378:metabolism; D005810:Multigene Family; D009154:Mutation; D010404:Penicillin V / Q000378:metabolism*; D010408:Penicillium chrysogenum / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D013172:Spores, Fungal / Q000254:growth & development*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D003470:Culture Media; D005656:Fungal Proteins; D014157:Transcription Factors; D010404:Penicillin V