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Thanatin targets the intermembrane protein complex required for lipopolysaccharide transport in Escherichia coli


Vetterli, Stefan U; Zerbe, Katja; Müller, Maik; Urfer, Matthias; Mondal, Milon; Wang, Shuang-Yan; Moehle, Kerstin; Zerbe, Oliver; Vitale, Alessandra; Pessi, Gabriella; Eberl, Leo; Wollscheid, Bernd; Robinson, John A (2018). Thanatin targets the intermembrane protein complex required for lipopolysaccharide transport in Escherichia coli. Science Advances, 4(11):eaau2634.

Abstract

With the increasing resistance of many Gram-negative bacteria to existing classes of antibiotics, identifying new paradigms in antimicrobial discovery is an important research priority. Of special interest are the proteins required for the biogenesis of the asymmetric Gram-negative bacterial outer membrane (OM). Seven Lpt proteins (LptA-G) associate in most Gram-negative bacteria to form a macromolecular complex spanning the entire envelope, which transports lipopolysaccharide (LPS) molecules from their site of assembly at the inner membrane to the cell surface, powered by adenosine 5′-triphosphate hydrolysis in the cytoplasm. The periplasmic protein LptA com- prises the protein bridge across the periplasm, which connects LptB2FGC at the inner membrane to LptD/E anchored in the OM. We show here that the naturally occurring, insect-derived antimicrobial peptide thanatin targets LptA and LptD in the network of periplasmic protein-protein interactions required to assemble the Lpt complex, leading to the inhibition of LPS transport and OM biogenesis in Escherichia coli.

Abstract

With the increasing resistance of many Gram-negative bacteria to existing classes of antibiotics, identifying new paradigms in antimicrobial discovery is an important research priority. Of special interest are the proteins required for the biogenesis of the asymmetric Gram-negative bacterial outer membrane (OM). Seven Lpt proteins (LptA-G) associate in most Gram-negative bacteria to form a macromolecular complex spanning the entire envelope, which transports lipopolysaccharide (LPS) molecules from their site of assembly at the inner membrane to the cell surface, powered by adenosine 5′-triphosphate hydrolysis in the cytoplasm. The periplasmic protein LptA com- prises the protein bridge across the periplasm, which connects LptB2FGC at the inner membrane to LptD/E anchored in the OM. We show here that the naturally occurring, insect-derived antimicrobial peptide thanatin targets LptA and LptD in the network of periplasmic protein-protein interactions required to assemble the Lpt complex, leading to the inhibition of LPS transport and OM biogenesis in Escherichia coli.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Uncontrolled Keywords:antibiotics thanatin LPS biogenesis beta-hairpin
Language:English
Date:2018
Deposited On:16 Nov 2018 13:28
Last Modified:16 Nov 2018 13:28
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
OA Status:Gold
Publisher DOI:https://doi.org/10.1126/sciadv.aau2634
Project Information:
  • : FunderSNSF
  • : Grant ID205320_146381
  • : Project TitleSynthetic Protein Epitope Mimetics and Applications as Anti-infectives
  • : FunderSNSF
  • : Grant ID31003A_160259
  • : Project TitleDirect identification of lateral protein interactions in the plasma membrane of living cells and tissues
  • : FunderETH grant
  • : Grant IDETH-30 17-1
  • : Project Title

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