Antibiotics are still the most important weapon for combatting bacterial infections. But medical science is running out of “ammunition” because of more and more frequently occurring resistances. Scientists from the Technical University of Munich and the Max Planck Institute of Molecular Physiology has now elucidated the structure of the proteolytic complex ClpX-ClpP. This is a key to development of innovative antibiotics which target the degradation process of defective proteins in bacteria.
Almost 700,000 people in Europe suffer from infections every year through antibiotic-resistant pathogens; approximately 33,000 of them die. Despite this enormous and globally increasing danger, very few new antibiotics have been developed and approved in the past few decades.
There is no improvement in sight. That is why it is urgently necessary to find new points of attack in pathogenic bacteria and to develop new antibiotics which exploit these weak spots.
New mechanism of action destroys bacteria
A particularly 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 ensures the controlled degradation of defective proteins.
But for this purpose it requires the ClpX protein as a starting aid. In the complex with ClpP, ClpX identifies proteins which should be degraded, unfurls them and guides them into its barrel-like degradation chamber.
Scientists in the groups led by Prof. Stephan Sieber, Technical University of Munich (TUM) and Prof. Stefan Raunser, Director at the Max Planck Institute of Molecular Physiology in Dortmund, have now elucidated the three-dimensional structure of the ClpX-ClpP proteolytic complex for the first time and thereby established an important basis for future pharmacological strategies.
A new class of potential antibiotics — the so-called acyldepsipeptide (ADEP) antibiotics — also brings about an uncontrolled degradation through ClpP without the support of ClpX. As a result also vital proteins are destroyed — with lethal consequences for the bacteria.
This unique mechanism of action has considerable innovation potential in the fight against pathogenic bacteria. Whereas common antibiotics act through the inhibition of vital processes, in this case the antibacterial effect is achieved through the activation of a process.