New antibiotic candidates from Braunschweig
Mode of action of HZI natural products elucidated – substances also act against bacteria that are resistant to antibiotics
A group of antibiotic natural products discovered at the Helmholtz Centre for Infection Research (HZI) in Braunschweig points out a new mode of action against pathogenic bacteria. Isolated from myxobacteria, the substances prevent an enzym of the pathogens from being able to translate their genetic material. In this way, the propagation of bacteria – such as tuberculosis pathogens - is inhibited. A working group at Rutgers University in New Jersey (USA) has now joined up with HZI researchers and discovered in detail how these compounds interact with the target in pathogenic bacteria. The novel target is different from the target of known antibiotics such as rifamycin, a standard medication to counteract tuberculosis.
This discovery makes the Braunschweig natural products extremely interesting candidates for a development as antibiotics – especially in view of the fact that the substances also kill bacterial strains that are resistant to antibiotics. Today, the scientists publish their results in the distinguished journal "Cell".
Antibiotics are an essential tool of medicine. We owe the antibiotics that diseases such as plague, cholera or tuberculosis are a thing of the past, at least in the industrialised world.
However, more and more bacteria are becoming resistant to medication. Consequently, doctors are in urgent need of new antibiotics. Their development is a demanding challenge: the drugs should attack the bacteria only but not interact with human cells. Subsequently, the number of effective antibiotic targets in bacteria is severely limited; every new active compound is warmly welcomed by the antibiotics researchers, especially if it highlights a new mode of action.
In the search for candidates which might be developed into such novel medicines the HZI enjoys a strong advantage: 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.en/metas/glossary/entry/pathogen-1/ 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 of the genetic materials is suppressed completely. This new mechanism also operates in bacteria that are resistant to conventional antibiotics.
For Jansen and Irschik the results of the US researchers signalize that their substances now are facing a long process of development: " In their present form myxopyronin, corallopyronin and ripostatin are not yet applicable as antibiotics," explains Irschik. Further chemical development is now required, as Jansen adds: "Our natural agents are so-called chemical leads, which the chemists will modify in detail in order to increase their antibiotic action and minimize side-effects. This development will include extensive testing, which may take several years, before the new medicine will reach the hands of doctors finally."
Title of original publication:
The RNA Polymerase “Switch Region” Is a Target for Inhibitors. Jayanta Mukhopadhyay, Kalyan Das, Sajida Ismail, David Koppstein, Minyoung Jang, Brian Hudson, Stefan Sarafianos, Steven Tuske, Jay Patel, Rolf Jansen, Herbert Irschik, Eddy Arnold and Richard H. Ebright; Cell, 17 October 2008 135: 295-307. DOI 10.1016/j.cell.2008.09.033