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

TitleInhibitor of intramembrane protease RseP blocks the σ response causing lethal accumulation of unfolded outer membrane proteins.
Publication TypeJournal Article
Year of Publication2018
AuthorsKonovalova, A, Grabowicz, M, Balibar, CJ, Malinverni, JC, Painter, RE, Riley, D, Mann, PA, Wang, H, Garlisi, CG, Sherborne, B, Rigel, NW, Ricci, DP, Black, TA, Roemer, T, Silhavy, TJ, Walker, SS
JournalProc Natl Acad Sci U S A
Date Published2018 Jun 25
ISSN1091-6490
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 stress response. When OMP folding defects arise, the proteases DegS and RseP act sequentially to liberate σ 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 activity in , 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 essentiality.

DOI10.1073/pnas.1806107115
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29941590