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Published online before print June 28, 2007, 10.1110/ps.072933007
Protein Science (2007), 16:1535-1542. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease

Lin Cheng1, Todd A. Naumann2,3, Alexander R. Horswill2,4, Sue-Jean Hong1,5, Bryan J. Venters1, John W. Tomsho2, Stephen J. Benkovic2, and Kenneth C. Keiler1

1 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
2 Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA

(RECEIVED April 6, 2007; FINAL REVISION April 25, 2007; ACCEPTED April 30, 2007)

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.

Keywords: cyclic peptide; ClpXP protease; antibacterial; protease inhibitor; SICLOPPS


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J. Bacteriol., November 1, 2007; 189(21): 7581 - 7585.
[Abstract] [Full Text] [PDF]


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