Protease inhibitors against antibiotic resistance
Two new strategies for fighting resistant bacteria
NanoNewsNet based on the materials of Technische Universitaet Muenchen: Two new weapons in the battle against bacteriaProteins consist of a chain of amino acids and play a vital role in all cellular processes.
One of the most important types of proteins are proteases. As "molecular scissors", they cut other proteins in certain places and thereby perform important functions. By cutting amino acid chains into segments of the desired length or destroying proteins, they, for example, activate or deactivate them or turn on signal sequences that serve to transport proteins to certain areas of the cell.
But proteases are important not only for human cells – bacteria also rely on them. In the fight against pathogens such as multi-resistant strains of Staphylococcus aureus or tuberculosis Mycobacterium tuberculosis, doctors have almost no effective antibiotics left.
Therefore, scientists around the world are persistently looking for new ways to destroy the proteases of these strains. Special attention is paid to the ClpP protease. It consists of 14 subunits and performs a central regulatory function.
(Photo: M. Gersch/TUM)
The usual approach to deactivating this protease is to block all its active centers. The active centers of ClpP can be called the cutting edges of scissors, i.e. the parts of the protein responsible for the destruction of other proteins.
"The inhibitors used in the past have one crucial drawback," explains Stephan Sieber, head of the Department of Organic Chemistry II at the Technical University of Munich (Technische Universitat Munchen, TUM). "They don't neutralize these proteins all the time, but only work for a few hours. In addition, to be effective, they must attack all the active centers of the protein."
In collaboration with Professor Michael Groll, head of the Department of Biochemistry, Malte Gersch and Roman Kolb, doctoral students of Professor Sieber's department, have discovered two completely new mechanisms that can be used to permanently deactivate this important bacterial protease. In one case, it does not even need to attack all the active centers of the protein.
The first mechanism disrupts the order of amino acids necessary for the coupling of protease subunits. As a result, the protease is split into two parts. The second one acts directly on the core of the active center. It converts the amino acid responsible for cleavage into another amino acid – the "scissors" lose their edge, and the protein – functionality. Both mechanisms inhibit proteases in a completely new way and, thus, are very promising for the development of new forms of drugs based on them.
Low molecular weight inhibitors either disrupt the order of amino acids necessary for the coupling of protein subunits,
or convert the amino acid responsible for cleavage into another amino acid.
Both variants lead to a loss of ClpP protease activity.
(Fig. Journal of the American Chemical Society)
In addition, scientists have discovered a number of inhibitors that initiate the work of these two mechanisms.
"The fact that we now know how these proteases are deactivated is a huge advance," says Hersh. "Now we can optimize these compounds and possibly apply this principle to other proteases as well."
In the future, Hersh and Sieber plan to test their low-molecular-weight inhibitors on live bacterial strains to determine whether they really inhibit the growth and pathogenic effect of bacteria.
"Although the bacteria are not completely disarmed, they produce significantly fewer toxins that cause inflammation," Hersh sums up. "The basic idea is that we suppress the emergence of new forms of resistance and thereby give the immune system more time to cope with pathogens on its own."
Article by Gersch et al. Disruption of Oligomerization and Dehydroalanine Formation as Mechanisms for ClpP Protease is published in the Journal of the American Chemical Society.
Portal "Eternal youth" http://vechnayamolodost.ru26.02.2014