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UdS > Pharmaceutical Biotechnology > Outline

Research

 

Research in the Müller group addresses the chemistry, biosynthesis, regulation, heterologous production and mode-of-action of secondary metabolites from myxobacteria and, more recently, actinomycetes.

Natural products (secondary metabolites) derived from microbes, plants and fungi, form the bedrock of the modern pharmaceutical industry. Among other activities, these compounds act as antibiotics (e.g. erythromycin,tetracycline), anti-cancer drugs (mitomycin, epothilone), cholesterol-lowering agents (lovastatin), immunosuppressants (rapamycin, cyclosporin), anti-parasitics (avermectin), and anti-diabetics (acarbose).

The soil-dwelling actinomycetes and myxobacteria are particularly notable microbial producers of natural products. We study the biosynthesis and regulation of secondary metabolism in these microorganisms, underpinning our efforts with whole-genome sequencing of model strains. We recently revealed, for example, that the myxobacterium Sorangium cellulosum has the largest bacterial genome yet discovered, as well as a capacity to produce natural products that far exceeds that revealed by standard natural products chemistry. The data we obtain allow us to optimize metabolite production in the native producers and express complete pathways in heterologous hosts (such as the Pseudomonads), as well as facilitating attempts to make predictable alterations to the structures by genetic engineering. Experiments are underway to ‘mine’ the sequenced genomes for novel compounds, using state-of-the-art analytical and statistical techniques, as well as to deepen our understanding of host microbiology through functional genomics (transcriptomics and proteomics).We also run a world-wide myxobacterial strain-discovery program, resulting in the identification of several new species, genera and families, as well as many potentially novel metabolites. Selected compounds are evaluated in mode-of-action studies, using a range of cell lines.

Members of this interdisciplinary group employ a broad spectrum of techniques, including microbiology, cell biology, genetics, molecular biology, protein chemistry, enzymology and analytical chemistry. We have also established multiple productive collaborations with academic and industrial partners (see ‘Cooperations’ on side bar).

Research Projects

Molecular and biochemical principles of secondary metabolite formation in myxobacteria and actinomycetes
A large portion of the work in the group addresses the genetics and mechanistic enzymology of natural product biosynthesis in myxobacteria and actinomycetes.  This work supports attempts to rationally modify the product structures by genetic engineering.

Kompetenzetzwerk ‘Genome Research on Bacteria Relevant for Agriculture, Environment and Biotechnology’ – the Sorangium genome project
This project exploits the data recently made available by the BMB+F-funded genome sequencing project of the model strain Sorangium cellulosum.  The genome is ‘mined’ for information relevant to optimizing natural product yields, as well as to generating new, biologically-active agents, using functional genomics approaches.

Myxobacterial strain discovery
We identify new myxobacterial strains from locations worldwide, using a set of efficient, in-house purification techniques.  The strains are then analyzed for the production of novel, bioactive compounds using (bioassay-guided) LC-MS.

Development of improved analytical and statistical methods for mining myxobacterial genomes
We support our genome mining efforts by developing LC-coupled high-resolution mass spectrometry methodologies, allied with advanced statistical approaches, such as principle component analysis.

Bioactivity and mode-of-action studies on myxobacterial metabolites and their analogues
Purified natural products and/or their synthetic analogues are evaluated against a collection of cancer-cell lines.  We investigate the mode-of-action of promising compounds using a range of cell biology techniques.

Biotechnological production of bromelain
The pineapple protein bromelain is a promising anti-inflammatory agent.  We are collaborating with Ursapharm Arzneimittel GmbH to develop methods for the recombinant production of bromelain, to enable its further development as a pharmaceutical agent.

 


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