Researchers Describe Novel Methods for Disabling Bacterial Proteases

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.”

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Technische Universitaet Muenchen