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Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):E6614-E6621. doi: 10.1073/pnas.1806107115. Epub 2018 Jun 25.

Inhibitor of intramembrane protease RseP blocks the σE response causing lethal accumulation of unfolded outer membrane proteins.

Author information

1
Department of Molecular Biology, Princeton University, Princeton, NJ 08540.
2
Department of Microbiology and Molecular Genetics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030.
3
Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA 30322.
4
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
5
Division of Infectious Disease, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322.
6
Merck & Co., Inc., Kenilworth, NJ 07033.
7
Hurley Consulting Associates Ltd., Summit, NJ 07901.
8
Department of Biology, Hofstra University, Hempstead, NY 11549.
9
Achaogen, Inc., South San Francisco, CA 94080.
10
Prokaryotics, Inc., Union, NJ 07083.
11
Department of Molecular Biology, Princeton University, Princeton, NJ 08540; tsilhavy@princeton.edu scott.walker@merck.com.
12
Merck & Co., Inc., Kenilworth, NJ 07033; tsilhavy@princeton.edu scott.walker@merck.com.

Abstract

The outer membrane (OM) of Gram-negative bacteria forms a robust permeability barrier that blocks entry of toxins and antibiotics. Most OM proteins (OMPs) assume a β-barrel fold, and some form aqueous channels for nutrient uptake and efflux of intracellular toxins. The Bam machine catalyzes rapid folding and assembly of OMPs. Fidelity of OMP biogenesis is monitored by the σE stress response. When OMP folding defects arise, the proteases DegS and RseP act sequentially to liberate σE into the cytosol, enabling it to activate transcription of the stress regulon. Here, we identify batimastat as a selective inhibitor of RseP that causes a lethal decrease in σE activity in Escherichia coli, and we further identify RseP mutants that are insensitive to inhibition and confer resistance. Remarkably, batimastat treatment allows the capture of elusive intermediates in the OMP biogenesis pathway and offers opportunities to better understand the underlying basis for σE essentiality.

KEYWORDS:

Bam complex; envelope stress response; protein folding; regulated proteolysis; signal transduction

PMID:
29941590
PMCID:
PMC6048503
DOI:
10.1073/pnas.1806107115
[Indexed for MEDLINE]
Free PMC Article

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