title: Inhibition of the β-barrel assembly machine by a peptide that binds BamD.
abstract: The protein complex that assembles integral membrane β-barrel proteins in the outer membranes of Gram-negative bacteria is an attractive target in the development of new antibiotics. This complex, the β-barrel assembly machine (Bam), contains two essential proteins, BamA and BamD. We have identified a peptide that inhibits the assembly of β-barrel proteins in vitro by characterizing the interaction of BamD with an unfolded substrate protein. This peptide is a fragment of the substrate protein and contains a conserved amino acid sequence. We have demonstrated that mutations of this sequence in the full-length substrate protein impair the protein's assembly, implying that BamD's interaction with this sequence is an important part of the assembly mechanism. Finally, we have found that in vivo expression of a peptide containing this sequence causes growth defects and sensitizes Escherichia coli to antibiotics to which they are normally resistant. Therefore, inhibiting the binding of substrates to BamD is a viable strategy for developing new antibiotics directed against Gram-negative bacteria.
authors: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; and.
authors: Christine L
authors: CL
authors: Hagan
authors: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; and.
authors: Joseph S
authors: JS
authors: Wzorek
authors: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 kahne@chemistry.harvard.edu.
authors: Daniel
authors: D
authors: Kahne
mesh_terms: D000595:Amino Acid Sequence; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
chemical_list: D001425:Bacterial Outer Membrane Proteins; C513739:BamD protein, E coli; D029968:Escherichia coli Proteins; D010455:Peptides
keywords: Bam complex; inhibition; outer membrane; protein folding; β-barrel
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