Activators of cylindrical proteases as antimicrobials: identification and development of small molecule activators of ClpP protease.

TitleActivators of cylindrical proteases as antimicrobials: identification and development of small molecule activators of ClpP protease.
Publication TypeJournal Article
Year of Publication2011
AuthorsLeung, E., A. Datti, M. Cossette, J. Goodreid, S. E. McCaw, M. Mah, A. Nakhamchik, K. Ogata, M. El Bakkouri, Y-Q. Cheng, S. J. Wodak, B. T. Eger, E. F. Pai, J. Liu, S. Gray-Owen, R. A. Batey, and W. A. Houry
JournalChem Biol
Volume18
Issue9
Pagination1167-78
Date Published2011 Sep 23
ISSN1879-1301
KeywordsAnti-Bacterial Agents, Binding Sites, Computer Simulation, Endopeptidase Clp, Enzyme Activation, Escherichia coli, Escherichia coli Proteins, Microbial Sensitivity Tests, Molecular Chaperones, Protein Structure, Tertiary, Recombinant Proteins, Small Molecule Libraries
Abstract

ClpP is a cylindrical serine protease whose ability to degrade proteins is regulated by the unfoldase ATP-dependent chaperones. ClpP on its own can only degrade small peptides. Here, we used ClpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five distinct compounds, which we designate as Activators of Self-Compartmentalizing Proteases 1 to 5 (ACP1 to 5). The compounds are found to stabilize the ClpP double-ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent classes of compounds that can activate ClpP and that can be developed as potential novel antibiotics.

DOI10.1016/j.chembiol.2011.07.023
Alternate JournalChem. Biol.
PubMed ID21944755
Grant List / / Canadian Institutes of Health Research / Canada