The weak point in pathogenic bacteria

Weak point in pathogenic bacteria
Antibiotics remain the most important weapon in fighting bacterial infections. But medicine is running out of "Ammunition" because resistance is more and more frequent.

Scientists from the Technical University of Munich and the Molecular Institute of Psychology have diluted the structure of the ClpX-ClpP proteolytic complex. 

Around 700,000 people in Europe suffer infections every year through antibiotic-resistant pathogens, approximately 33,000 of those people die. 

Despite this enormous and growing danger worldwide, very few antibiotics have been developed and approved in recent decades.

There is no improvement in sight. This is because it is urgently necessary to find new attack points in pathological bacteria and develop new antibiotics that take advantage of these weak points.

An especially promising point of attack for antibacterial therapies is the proteolytic enzyme ClpP: on the one hand, it plays an important role in bacterial metabolism, and on the other hand, it guarantees the controlled degradation of defective proteins.

But for this purpose, the ClpX protein is required as an initial aid. 
In a complex with ClpP, ClpX identifies the proteins to be degraded, unfolds them, and guides them into its barrel-shaped degradation chamber.

A group of scientists led by Prof. Stephan Sieber, from the Technical University of Munich (TUM) and Prof. Stefan Raunser, Director at the Max Planck of the Molecular Psychological Institute in Dortmund, has now elucidated the three-dimensional structure of the ClpX -ClpP for the first time and thus established an important foundation for future drug strategies.

A new class of potential antibiotics - called acyldepsipeptide antibiotic (ADEP) also causes uncontrolled degradation through ClpP without the support of ClpX. As a result, vital proteins are also destroyed, with lethal consequences for bacteria.

This unique mechanism of action has been considered a powerful innovation in the fight against pathological bacteria. Whereas common antibiotics act by inhalation of vital processes.

In addition to the degradation of defective proteins, ClpP is also a decisive regulator in the production of an arsenal of bacterial toxins that are responsible for the pathogenic effect of many pathogens.

At the Technical University of Munich, the group led by Prof. Stephan Sieber has been successfully investigating the ClpP protein for years and has already developed a large number of potent inhibitors against ClpP and ClpX that stop the production of bacterial toxins. 

Therefore can more or less disarm them. Dora Balogh has now managed to produce and stabilize the ClpX-ClpP complex.

But until recently the structure of the ClpX-ClpP complex may not yet be elucidated in detail. 

Dr. Christos Gatsogiannis, a researcher in the group led by Stefan Raunser at the MPI for Molecular Psychology, has achieved this in the group using cryogenic electron microscopy.

With this technology, they were able to demonstrate that ADEP and ClpX couple to ClpP at the same point, but in the protein degradation process in a different way: While ClpX does not cause an alteration in the structure of ClpP, ADEP produces an opening involuntary complex.

As a result, intact proteins are also degraded uncontrollably and without ClpX support. 

This mechanism by research teams from Dortmund and Munich is a milestone on the path of developing innovative antibiotic substances targeting ClpP.
The weak point in pathogenic bacteria The weak point in pathogenic bacteria Reviewed by Muhammad Akram on April 22, 2021 Rating: 5

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