Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease

Lin Cheng, Todd A. Naumann, Alexander R. Horswill, Sue Jean Hong, Bryan J. Venters, John W. Tomsho, Stephen Benkovic, Kenneth Charles Keiler

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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. Published by Cold Spring Harbor Laboratory Press.

Original languageEnglish (US)
Pages (from-to)1535-1542
Number of pages8
JournalProtein Science
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2007

Fingerprint

Cyclic Peptides
Peptide Hydrolases
Escherichia coli
Caulobacter crescentus
Proteolysis
Escherichia coli Proteins
Enzyme Inhibitors
Ports and harbors
Bioactivity
Protease Inhibitors
Sorting
Flow Cytometry
Fluorescence
Cells
Degradation
Molecules
Substrates
Enzymes
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

Cite this

Cheng, L., Naumann, T. A., Horswill, A. R., Hong, S. J., Venters, B. J., Tomsho, J. W., ... Keiler, K. C. (2007). Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease. Protein Science, 16(8), 1535-1542. https://doi.org/10.1110/ps.072933007
Cheng, Lin ; Naumann, Todd A. ; Horswill, Alexander R. ; Hong, Sue Jean ; Venters, Bryan J. ; Tomsho, John W. ; Benkovic, Stephen ; Keiler, Kenneth Charles. / Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease. In: Protein Science. 2007 ; Vol. 16, No. 8. pp. 1535-1542.
@article{3817f4bac7be4ec5815e7351074a3377,
title = "Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease",
abstract = "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. Published by Cold Spring Harbor Laboratory Press.",
author = "Lin Cheng and Naumann, {Todd A.} and Horswill, {Alexander R.} and Hong, {Sue Jean} and Venters, {Bryan J.} and Tomsho, {John W.} and Stephen Benkovic and Keiler, {Kenneth Charles}",
year = "2007",
month = "8",
day = "1",
doi = "10.1110/ps.072933007",
language = "English (US)",
volume = "16",
pages = "1535--1542",
journal = "Protein Science",
issn = "0961-8368",
publisher = "Cold Spring Harbor Laboratory Press",
number = "8",

}

Cheng, L, Naumann, TA, Horswill, AR, Hong, SJ, Venters, BJ, Tomsho, JW, Benkovic, S & Keiler, KC 2007, 'Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease', Protein Science, vol. 16, no. 8, pp. 1535-1542. https://doi.org/10.1110/ps.072933007

Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease. / Cheng, Lin; Naumann, Todd A.; Horswill, Alexander R.; Hong, Sue Jean; Venters, Bryan J.; Tomsho, John W.; Benkovic, Stephen; Keiler, Kenneth Charles.

In: Protein Science, Vol. 16, No. 8, 01.08.2007, p. 1535-1542.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease

AU - Cheng, Lin

AU - Naumann, Todd A.

AU - Horswill, Alexander R.

AU - Hong, Sue Jean

AU - Venters, Bryan J.

AU - Tomsho, John W.

AU - Benkovic, Stephen

AU - Keiler, Kenneth Charles

PY - 2007/8/1

Y1 - 2007/8/1

N2 - 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. Published by Cold Spring Harbor Laboratory Press.

AB - 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. Published by Cold Spring Harbor Laboratory Press.

UR - http://www.scopus.com/inward/record.url?scp=34547561306&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547561306&partnerID=8YFLogxK

U2 - 10.1110/ps.072933007

DO - 10.1110/ps.072933007

M3 - Article

VL - 16

SP - 1535

EP - 1542

JO - Protein Science

JF - Protein Science

SN - 0961-8368

IS - 8

ER -

Cheng L, Naumann TA, Horswill AR, Hong SJ, Venters BJ, Tomsho JW et al. Discovery of antibacterial cyclic peptides that inhibit the ClpXP protease. Protein Science. 2007 Aug 1;16(8):1535-1542. https://doi.org/10.1110/ps.072933007