Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New agents to combat the plague

11.01.2012
The plague is believed to have been eradicated in Europe. But it continues to reappear in other parts of the world, such as Madagascar, the Congo, and Peru. Since the pathogens are becoming resistant to the usual antibiotics, new agents are urgently needed. Progress has now been made in this area.

A wonderful breakthrough for scientists from the universities of Würzburg and Stony Brook (USA): they have shed light on the binding and action mechanisms of two new inhibitors that attack the plague pathogen, the bacterium Yersinia pestis. In the current issue of the journal “Structure” they present both substances, which belong to the pyridone group.


A newly developed inhibitor (magenta) from the pyridone group binds to a vital enzyme of the plague pathogen. The cofactor of the enzyme, NADH, which contributes significantly to the effect of the inhibitor, is shown in blue.
Image: Maria Hirschbeck

The new inhibitors attach themselves to the bacterial enzyme FabV and impede it in its work. This enzyme performs the final step in the production of bacterial fatty acids. If it is blocked, the plague pathogen dies. This is because without fatty acids it cannot maintain its protective shell, the cell membrane.

“But the two substances do not inhibit the enzyme well enough yet,” says Professor Caroline Kisker of the Rudolf Virchow Center at the University of Würzburg. For that reason, these new inhibitors and their interactions with the enzyme now need to be analyzed further and improved.

Steps to improve the inhibitors

Structural biologist Kisker, her doctoral student Maria Hirschbeck, and postdoctoral fellow Jochen Kuper are collaborating on this with Würzburg chemists and pharmacists Professor Christoph Sotriffer and Steffen Wagner as well as with Peter Tonge of Stony Brook University. In their laboratories, these scientists are working not with pathogens of the plague, but with the isolated enzyme. They are crystallizing it as a compound with the inhibitors, rendering it into a state in which they can analyze how the inhibitors attach themselves to the enzyme right down to the molecular level.

Christoph Sotriffer, an expert in computer modeling of molecules, and his staff then examine the crystal structures and propose changes to the inhibitors that might make these even more effective. Finally, the modified inhibitors are synthesized and re-tested: test-tube experiments reveal whether they really are further weakening this enzyme that is so vital to the plague pathogen.

“This cycle will generally have to be repeated several times until, ideally, we end up with a highly active inhibitor,” says Caroline Kisker. However, whether the inhibitor will then also be suitable as medication is far from certain. Numerous other tests will be needed to determine that.

This research is contained within the Würzburg Collaborative Research Center 630 (Recognition, Preparation, and Functional Analysis of Agents against Infectious Diseases). The German Research Foundation (DFG) is funding the work.

Progression of an infection with the plague pathogen

The pathogens of the plague tend to live in rodents, particularly rats. They can be transferred to humans through bites from infected rat fleas. After one to seven days, the sufferer develops a high fever and shivering, among other things. These symptoms are joined by painful buboes, swellings of the lymph nodes that appear like lumps on the skin. In rare cases, the lumps rupture outwards, according to the Robert Koch Institute.

As the disease progresses, the pathogens may also attack internal organs, especially the lungs. It is then common for the sufferer to cough up blood. At this stage, the pathogens can also be transmitted from human to human in droplets of coughed-up fluid. Without treatment with antibiotics, this pneumonic plague, as it is known, almost always ends in death. With bubonic plague, on the other hand, there is a 50 percent chance of survival even without treatment. Generally speaking, if the plague is detected early, it can be treated successfully with antibiotics – provided that these are still effective.

Resistant plague pathogens discovered

In 2010, scientists from the Pasteur Institute in Paris found two plague pathogen strains that no longer respond to antibiotics. Both came from Madagascar. This island south-east of Africa is a hotspot for global outbreaks of the plague: in 2010, there were 313 recognized cases of the disease here, according to statistics from the World Health Organization (WHO). The second-highest incidence of infection was found in the Congo (152), followed by Peru with 27 cases.

“Structure of the Yersinia pestis FabV Enoyl-ACP Reductase and its Interaction with two 2-Pyridone Inhibitors”, Maria W. Hirschbeck, Jochen Kuper, Hao Lu, Nina Liu, Carla Neckles, Sonam Shah, Steffen Wagner, Christoph A. Sotriffer, Peter J. Tonge, and Caroline Kisker. Structure, Vol. 20, Issue 1, 89-100, 11 January 2012, DOI 10.1016/j.str.2011.07.019

Contact

Prof. Dr. Caroline Kisker, Institute of Structural Biology, Rudolf Virchow Center / DFG Research Center for Experimental Biomedicine, T +49 (0)931 31-80381, caroline.kisker@virchow.uni-wuerzburg.de

Robert Emmerich | Julius-Maximilians-Universität W
Further information:
http://www.virchow.uni-wuerzburg.de

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Supersensitive through quantum entanglement

28.06.2017 | Physics and Astronomy

X-ray photoelectron spectroscopy under real ambient pressure conditions

28.06.2017 | Physics and Astronomy

Mice provide insight into genetics of autism spectrum disorders

28.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>