학술논문
Inhibitor of intramembrane protease RseP blocks the σ E response causing lethal accumulation of unfolded outer membrane proteins.
Document Type
Academic Journal
Author
Konovalova A; Department of Molecular Biology, Princeton University, Princeton, NJ 08540.; Department of Microbiology and Molecular Genetics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030.; Grabowicz M; Department of Molecular Biology, Princeton University, Princeton, NJ 08540.; Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA 30322.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.; Division of Infectious Disease, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322.; Balibar CJ; Merck & Co., Inc., Kenilworth, NJ 07033.; Malinverni JC; Merck & Co., Inc., Kenilworth, NJ 07033.; Painter RE; Merck & Co., Inc., Kenilworth, NJ 07033.; Riley D; Merck & Co., Inc., Kenilworth, NJ 07033.; Mann PA; Merck & Co., Inc., Kenilworth, NJ 07033.; Wang H; Merck & Co., Inc., Kenilworth, NJ 07033.; Garlisi CG; Merck & Co., Inc., Kenilworth, NJ 07033.; Hurley Consulting Associates Ltd., Summit, NJ 07901.; Sherborne B; Merck & Co., Inc., Kenilworth, NJ 07033.; Rigel NW; Department of Molecular Biology, Princeton University, Princeton, NJ 08540.; Department of Biology, Hofstra University, Hempstead, NY 11549.; Ricci DP; Department of Molecular Biology, Princeton University, Princeton, NJ 08540.; Achaogen, Inc., South San Francisco, CA 94080.; Black TA; Merck & Co., Inc., Kenilworth, NJ 07033.; Roemer T; Merck & Co., Inc., Kenilworth, NJ 07033.; Prokaryotics, Inc., Union, NJ 07083.; Silhavy TJ; Department of Molecular Biology, Princeton University, Princeton, NJ 08540; tsilhavy@princeton.edu scott.walker@merck.com.; Walker SS; Merck & Co., Inc., Kenilworth, NJ 07033; tsilhavy@princeton.edu scott.walker@merck.com.
Source
Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Subject
Language
English
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 σ E stress response. When OMP folding defects arise, the proteases DegS and RseP act sequentially to liberate σ E 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 σ E 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 σ E essentiality.
Competing Interests: Conflict of interest statement: C.J.B., J.C.M., R.E.P., D.R., P.A.M., H.W., C.G.G., B.S., T.A.B., T.R., and S.S.W. are, or were at the time this work was conducted, employees of Merck & Co., Inc. and may be shareholders. Research was supported by internal Merck funds. T.J.S. was supported by a grant from Merck & Co., Inc.
Competing Interests: Conflict of interest statement: C.J.B., J.C.M., R.E.P., D.R., P.A.M., H.W., C.G.G., B.S., T.A.B., T.R., and S.S.W. are, or were at the time this work was conducted, employees of Merck & Co., Inc. and may be shareholders. Research was supported by internal Merck funds. T.J.S. was supported by a grant from Merck & Co., Inc.