title: A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli.
abstract: Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM.
authors.affiliation: From the Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich.
authors.forename: Matthias
authors.initials: M
authors.lastname: Urfer
authors.affiliation: From the Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Bogdanovic
authors.affiliation: From the Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich.
authors.forename: Fabio
authors.initials: F
authors.lastname: Lo Monte
authors.affiliation: From the Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Moehle
authors.affiliation: From the Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich.
authors.forename: Katja
authors.initials: K
authors.lastname: Zerbe
authors.affiliation: the Institute of Molecular Systems Biology, ETH Zurich, Auguste-Piccard Hof 1, 8093 Zurich, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Omasits
authors.affiliation: the Institute for Plant Production Sciences, Research Group Molecular Diagnostics, Genomics, and Bioinformatics and the Swiss Institute of Bioinformatics, Agroscope, Schloss 1, 8820 Wädenswil, Switzerland, and.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Ahrens
authors.affiliation: the Department of Microbiology, Institute of Plant Biology, University of Zurich, Zollikerstrasse 107, 8008 Zurich, Switzerland.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pessi
authors.affiliation: the Department of Microbiology, Institute of Plant Biology, University of Zurich, Zollikerstrasse 107, 8008 Zurich, Switzerland.
authors.forename: Leo
authors.initials: L
authors.lastname: Eberl
authors.affiliation: From the Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich,. Electronic address: robinson@oci.uzh.ch.
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D057786:Peptidomimetics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D010455:Peptides; D057786:Peptidomimetics
keywords: Gram-negative bacteria; antibiotic action; membrane protein; outer membrane; peptides