Features | Partner Sites | Information | LinkXpress
Sign In
JIB
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING

Researchers Describe Novel Methods for Disabling Bacterial Proteases

By BiotechDaily International staff writers
Posted on 27 Feb 2014
Image: The target: bacterial protease ClpP (Photo courtesy of Technische Universitaet Muenchen).
Image: The target: bacterial protease ClpP (Photo courtesy of Technische Universitaet Muenchen).
Image: Several small molecules are able to split the protease ClpP into inactive smaller units, which massively disturbs the bacterial metabolism ClpP (Photo courtesy of Technische Universitaet Muenchen).
Image: Several small molecules are able to split the protease ClpP into inactive smaller units, which massively disturbs the bacterial metabolism ClpP (Photo courtesy of Technische Universitaet Muenchen).
A paper described previously unrecognized mechanisms that can be used to permanently deactivate critical bacteriological proteases.

Proteases are responsible for the pathogenic effects of many kinds of bacteria, and considerable research effort is involved in developing effective ways of inhibiting their action.

Investigators at the Technische Universitaet Muenchen (Munich, Germany) recently described novel approaches for silencing the activity of bacterial ClpP protease. In the January 29, 2014, issue of the Journal of the American Chemical Society they presented a novel mechanism of protease inhibition that relied on active-site-directed small molecules that disassembled the protease complex. They showed the applicability of this mechanism within the ClpP protease family, whose members are tetradecameric serine proteases and serve as regulators of several cellular processes, including homeostasis and virulence.

In addition, they reported the selective beta-sultam-induced dehydroalanine formation of the active site serine. This reaction proceeded through sulfonylation and subsequent elimination, thereby obliterating the catalytic charge relay system. The identity of the dehydroalanine was confirmed by mass spectrometry and crystallography. Activity-based protein profiling experiments suggested the formation of a dehydroalanine moiety in living Staphylococcus aureus cells upon beta-sultam treatment.

The mechanisms described here point towards the possibility of developing protease inhibitors that do not rely on complete blocking of the enzymes' catalytic or binding sites.

“ClpP inhibitors used in the past have one decisive disadvantage,” said senior author Dr. Stephan Sieber, professor of organic chemistry at the Technische Universitaet Muenchen. “They do not permanently disarm the proteins, but only work for a few hours. On top of that, to be effective they must attack all active centers of the protein.”

Related Links:

Technische Universitaet Muenchen



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: S-649266 has more robust antibacterial activity than established antibiotics against multidrug-resistant bacteria (Photo courtesy of Shionogi).

Novel Antibiotic Shows Potential for Broad Range of Infections

The emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating the infection caused by multi drug resistant (MDR) bacteria. In order to treat bacterial... Read more

Business

view channel

Collaboration of Mayo Clinic and IBM Cognitive Computer Devised to Improve Clinical Trial Research

The Mayo Clinic (Rochester, MN, USA) and IBM (Armonk, NY, USA) recently announced plans to pilot Watson, the IBM cognitive computer, to match patients more rapidly with suitable clinical trials. A proof-of-concept phase is currently ongoing, with the intent to introduce it into clinical use in early 2015.... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.