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

Publication Year
2018

Type

Journal Article
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.

Journal
Proc Natl Acad Sci U S A
Volume
115
Issue
28
Pages
E6614-E6621
Date Published
2018 Jul 10
ISSN Number
1091-6490
Alternate Journal
Proc Natl Acad Sci U S A
PMCID
PMC6048503
PMID
29941590