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

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.

authors

Konovalova 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

doi

10.1073/pnas.1806107115

subject

Has Abstract

pub_date

2018-07-10 00:00:00

pages

E6614-E6621

issue

28

eissn

0027-8424

issn

1091-6490

pii

1806107115

journal_volume

115

pub_type

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