Many pathogens are able to generate resistances against drugs like antibiotics leading to an uncontrolled spreading of pathogenic strains. However, an efficient treatment of numerous diseases is missing due to the lack of specific drugs. Therefore, a major task in pharmaceutical research is the identification and development of new agents. Interesting targets are natural products, so-called secondary metabolites, synthesized by microbes, plants and fungi. These agents can, for example, act as antibiotics, anti-cancer drugs, cholesterol-lowering agents, immunosuppressants, anti-parasitics and anti-diabetics.
One of the large-scale producers of natural products are myxobacteria, which are living in soil and secrete a number of compounds not only to kill their microbial competitors or enemies. The department “Microbial Natural Products” investigates the chemistry, production, regulation and mode-of-action of secreted metabolites from myxobacteria and, more recently, also from other natural producers such as actinomycetes, a different type of soil-living bacteria.
The scientists study the secondary metabolism in these microorganisms underpinning their efforts with whole-genome sequencing of model strains. Recently, they revealed the largest bacterial genome yet discovered in the myxobacterium Sorangium cellulosum. This bacterium has a huge capacity to produce natural products. The data allow the optimization of metabolite production in these microbes and the expression of complete pathways in heterologous hosts. Furthermore, it is possible to perform predictable alterations to the agents’ structures by genetic engineering. Experiments are underway to “mine” the sequenced genomes for novel compounds using state-of-the-art analytical techniques as well as to deepen the understanding of host microbiology.
The scientists also run a world-wide myxobacterial strain-discovery program, which results in the identification of new myxobacterial species, genera and families. Once a new strain has been successfully adapted to growth under laboratory conditions, we use state-of-the-art mass spectrometric techniques to screen the strain's metabolite profile with respect to the presence of known myxobacterial secondary metabolites. At the same time we perform a range of biological assays, using indicator organisms as well as cell-based screening approaches to discover novel compounds exhibiting a potentially interesting activity. Following optimization of the production of candidate compounds, cultivation of the producing strain is upscaled and the target compounds are purified using liquid chromatography methods. Thereafter, structure elucidation using a panel of analytical techniques including multidimensional NMR spectroscopy is carried out. In addition, further cell-based experiments are performed in order to investigate in detail the mode-of-action of a novel natural product.
Scientists in the interdisciplinary research group combine a broad spectrum of techniques including microbiological, molecular-biological, genetic, biochemical, analytical and bioengineering methods.
A current overview of the team and further information about the research group can be found on the HIPS page.