The work of Professor Michael Müller and Dr. Pascal Dünkelmann uses nature as a model. The company Codexis, as well as Müller’s research group at the University of Freiburg, are looking for “intelligent” methods for the recovery and production of pharmaceutical substances. They hope to establish production processes that are environmentally friendly, save resources and are as cheap as possible. What could be a better source of ideas than nature?

The cooperation between the Jülich-based company, which was acquired by the Californian Codexis Group in 2002, and the pharmaceutical chemists in Freiburg works extremely well. Ideas and enzymes are exchanged between scientists from both groups. Enzymes are proteins that make chemical reactions possible; they accelerate the development of a desired substance. That is why experts prefer to refer to them as catalysts. For example, Codexis sends enzymes to Freiburg where they are investigated closely: How active are the enzymes? Which substances can they convert under different conditions? What kinds of products do they generate? The results often lead to new cooperations.

At the recent “Science meets Business Day”, the two partners presented a concrete example of successful cooperation, i.e. one with big economic potential: Over the last few years, the cholesterol-reducing drug “Atvorvastin” has been one of the most important on the market. In 2006 alone, the drug generated revenues of more than 12 billion US dollars.

Codexis and Müller’s group of researchers are working on the optimisation of methods that enable the synthesis of side chains of the cholesterol-reducing drug. In economic terms, this is of major interest since tons of this side chain are required in pharmaceutical production. Müller knew that callystatin, a natural product produced by marine sponges used in cancer therapy, had this structural feature. Inspired by this natural process, Müller succeeded in developing a new synthesis pathway for this important component. As in many previous projects, Müller was once again able to show that nature does not follow linear production pathways. Enzymatic methods enable the production of the sought-after substance as well as three further interesting bioactive products.

The work of Professor Andreas Bechthold and Professor Dirk Bumann focuses on the search for new antibiotics. After half a century, in which it seemed largely possible to treat and combat infectious diseases, the importance of new antibiotics is increasing. Diseases such as tuberculosis are returning and bacteria are to a growing extent insensitive to antibiotics. Resistant Staphylococcus strains – MRSA – are especially troublesome in hospital-associated infections. On the other hand, it takes a long time to develop new antibiotics. Since 2002, only two new substances have been approved for human application.

There is a simple reason why scientists find it difficult to discover new antibiotics: Bacteria only have a handful of indispensable metabolic pathways that need to function in order to secure the survival of the pathogens. This means that there are only a few points in the life cycle of E. coli and other bacteria where antibiotic substances can effectively interfere. Dirk Bumann spoke about “incredibly robust biological networks” when talking about bacteria and their enzymes. The scientists had investigated 2,200 Salmonella enzymes and were unable to discover a single one that would have been a promising candidate for antibiotic intervention. That’s why they have to look at well-known pathways; for example, Bumann is using innovative methods to search for elements in bacterial genomes that regulate the assembly of the cell wall and which might be prone to antibiotic intervention.

Bechthold is aware of some promising candidates thanks to another strategy that focuses on the rediscovery of old antibiotics. The Berlin-based company Combinature Biopharm, which was established by Bechthold and some other scientists, has recently been able to show that this is indeed possible. Initial results showed that an antibiotic substance that prevents the assembly of the bacterial cell wall is associated with life-threatening side effects. The project was abandoned. However, the substance received a second chance in the laboratories of Combinature Biopharm. Modifications of the lipopeptide antibiotic eradicated the harmful effects of the drug. In July 2007, clinical trials were started to assess the effect and safety of the drug.

Moreover, there are some more ways to create new antibiotics. New bacteria were discovered in ecological niches, for example, on the deep-sea floor, that could potentially produce new antibiotics. And the researchers also believe in the positive potential of bacterial genome research, in which they are looking at the gene sequences of natural antibiotics producers in order to produce copies of natural substances and build basic structures with antibiotic activity. The researchers are creating new production pathways for bioactive substances and biotechnological modifications enable bacteria to produce several dozens of new substances. Bumann and Bechthold are hoping to combine their fields of research – the screening of new elements that might be sensitive to antibiotic intervention, and the establishment of new methods for the generation of new natural substances – and establish the “Freiburg Antibiotics Factory” sometime in 2008.

kb – 04.02.2008
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