Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease.

Cheng L, Naumann TA, Horswill AR, Hong SJ, Venters BJ, Tomsho JW, Benkovic SJ, Keiler KC
Protein Sci. 2007 16 (8): 1535-42

PMID: 17600141 · PMCID: PMC2203360 · DOI:10.1110/ps.072933007

A method to rapidly screen libraries of cyclic peptides in vivo for molecules with biological activity has been developed and used to isolate cyclic peptide inhibitors of the ClpXP protease. Fluorescence activated cell sorting was used in conjunction with a fluorescent reporter to isolate cyclic peptides that inhibit the proteolysis of tmRNA-tagged proteins in Escherichia coli. Inhibitors shared little sequence similarity and interfered with unexpected steps in the ClpXP mechanism in vitro. One cyclic peptide, IXP1, inhibited the degradation of unrelated ClpXP substrates and has bactericidal activity when added to growing cultures of Caulobacter crescentus, a model organism that requires ClpXP activity for viability. The screen used here could be adapted to identify cyclic peptide inhibitors of any enzyme that can be expressed in E. coli in conjunction with a fluorescent reporter.

MeSH Terms (10)

Anti-Bacterial Agents Bacterial Proteins Caulobacter crescentus Endopeptidase Clp Luminescent Proteins Models, Biological Peptide Library Peptides, Cyclic Protease Inhibitors Substrate Specificity

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