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New antibiotic candidates from Braunschweig
Date:10/17/2008

the institute has a unique collection of natural substances which has proved to be a highly effective source of drug candidates in the past. For example, the collection provided epothilone, which was approved as cancer medication last year. These substances are produced by myxobacteria, a group of microorganisms living in the soil.

The origin of the current success story is outlined by HZI biologist Dr. Herbert Irschik: "In our fundus we have three substances myxopyronin, corallopyronin and ripostatin which were isolated and characterised chemically and biologically. Already many years ago we recognized their unusual antibiotic effect. It was directed in an unknown manner against the bacterial RNA polymerase, i.e. the enzyme that reads the DNA of the pathogen. In eukaryontic cells, which human cells are also belonging to, the substances do not attack the RNA polymerase." However, before the initial evidence turned the substances into true antibiotic candidates, scientists had to reveal precisely how the growth of the bacteria was inhibited. "We began to develop a biotechnological processes which enabled us to produce and isolate the myxobacterial natural substances in large quantities," explains HZI chemist Dr. Rolf Jansen, who was also involved in the study.

Afterwards, the collaboration with the US research group at Rutgers University came off. The structural biologists studied the interaction of the HZI substances with the RNA polymerase. The results supported the indication that the natural substances block the bacterial RNA polymerase in a new manner: the natural substances append to another location within the RNA polymerase than the antibiotics previously investigated.

They attach to the enzyme which looks like an open crab claw directly at its joint position. Subsequently the enzyme is no longer able to open the claw. By this mechanism of action the active substances prevent the RNA polymerase from adhering to the DNA reading
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Contact: Hannes Schlender
hannes.schlender@helmholtz-hzi.de
49-531-618-11400
Helmholtz Association of German Research Centres
Source:Eurekalert

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