Systems Biology of the Secondary Metabolism in Filamentous Fungi
Doktorsavhandling, 2018

Filamentous fungi constitute a rich reservoir of pharmaceutically relevant bioactive small molecules. These compounds, commonly referred to as secondary metabolites, are widely used as antibiotics for the treatment of microbial infections, but also as other pharmaceuticals such as immunosuppressors, cholesterol lowering agents and anticancer drugs. Although fungal derived antibiotics have been known for almost a century, genome sequencing has revealed that the biosynthetic potential of fungi is not fully exhausted. The Penicillium genus consists of around 350 accepted species, and many of these are well-known producers of pharmaceuticals and industrially exploited for this. The genus as a whole, however, is grossly understudied at the genomic level. To assess the potential for secondary metabolite biosynthesis in the Penicillium genus, we sequenced the genomes of ten species that produce diverse arrays of secondary metabolites in culture. One of the sequenced isolates was described as a new species, and we mapped secondary metabolites detected in culture to the corresponding biosynthetic gene clusters. The ten sequenced genomes were analyzed together with published Penicillium genomes, altogether 24, and we developed a pipeline to group biosynthetic gene clusters and map them to known pathways. We found a large untapped potential for biosynthesis of secondary metabolites, encoded in the genomes of these species, that potentially could fill the drug discovery pipeline. Based on our predictions, we experimentally identified a novel compound from the antifungal class of antibiotics called yanuthones. Since heterologous expression of secondary metabolite pathways has proved troublesome, the ten genome-sequenced Penicillium species were evaluated as cell factories in controlled bioreactor fermentations. Compared to an industrially relevant strain, the ten Penicillium species showed growth characteristics that encourage further exploration of their industrial potential. Transcriptome analysis of six of the species enabled the identification of a metabolic network that is responsible for precursor formation of secondary metabolites. This network provides important insight into the further industrial development of Penicillium cell factories, and could be used in designing metabolic engineering strategies for optimization of secondary metabolite production. Altogether this thesis provides novel insights into genetic and metabolic aspects of fungal secondary metabolism. Our findings propose that industrial production of secondary metabolites can be effectively established on the basis of native producers. Penicillium species constitute a rich source of drug leads, and possess promising physiological characteristics to be established as industrial production platforms.


systems biology

secondary metabolites


Next-generation sequencing

secondary metabolism

filamentous fungi

cell factories


Sal KA, Kemihuset (Chalmers, Johanneberg campus)
Opponent: Mikael Rørdam Andersen, Technical University of Denmark


Jens Christian Froslev Nielsen

Chalmers, Biologi och bioteknik, Systembiologi

Physiological characterization of secondary metabolite producing Penicillium cell factories

Fungal Biology and Biotechnology,; Vol. 4(2017)p. 8-

Artikel i vetenskaplig tidskrift

Nielsen, J. C., Prigent, S., Grijseels, S., Workman, M., Ji, B., Nielsen, J. (2018). Metabolic regulation of filamentous fungi is tailored for production of secondary metabolites.

Prigent, S., Nielsen, J. C., Frisvad, J. C., and Nielsen, J. (2018). Automatic reconstruction of 24 Penicillium genome-scale metabolic models shows diversity in the secondary metabolism.

Microbes can thrive in most environments on earth, and niches such as soil and decaying plant material are biological hotspots of microbial diversity. These habitats constitute ecological battlegrounds where microorganisms fight for the same limited resources. In order to get first right to nutrients, microbes have evolved chemical weaponry to fight off competitors. These chemicals have been designed by the natural processes of randomization and selection to specifically target weak points of competitors, while leaving the producing organism unharmed. Such naturally derived chemicals can be exploited by humans as pharmaceuticals such as antibiotics.

This PhD thesis represents an endeavour to increase the understanding of the natural production of antibiotics in filamentous fungi. We provide novel insight on how to speed up the drug discovery process, from screening of microbial biodiversity to industrial exploitation. The genomes of uncharacterized filamentous fungi were sequenced, and a computational analysis pipeline was developed to identify and annotate the genes responsible for the synthesis of antibiotics. Our investigations demonstrated that fungal biodiversity possesses a previously untapped potential for production of antibiotics, and based on our predictions, we experimentally identified a novel compound from the antifungal class of antibiotics called yanuthones.

Further investigations of fungal metabolism were based on the quantification of gene expression, and allowed us to identify important pathways that provide building blocks for the biosynthesis of antibiotics. Modifying the genes controlling these pathways constitute a promising strategy for improving the natural production capabilities of fungi to enable industrial production of new antibiotics.

This thesis suggests that previously unknown antibiotics can be discovered from understudied fungi, and that genetic modifications of key metabolic pathways identified in this work, could enable development of industrial antibiotics production processes.




Bioinformatik och systembiologi



C3SE (Chalmers Centre for Computational Science and Engineering)


Innovation och entreprenörskap


Livsvetenskaper och teknik (2010-2018)



Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 4352



Sal KA, Kemihuset (Chalmers, Johanneberg campus)

Opponent: Mikael Rørdam Andersen, Technical University of Denmark

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