9co2

Publication Abstract from PubMed

BamA is the central component of the essential beta-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds beta-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

The discovery and structural basis of two distinct state-dependent inhibitors of BamA.,Sun D, Storek KM, Tegunov D, Yang Y, Arthur CP, Johnson M, Quinn JG, Liu W, Han G, Girgis HS, Alexander MK, Murchison AK, Shriver S, Tam C, Ijiri H, Inaba H, Sano T, Yanagida H, Nishikawa J, Heise CE, Fairbrother WJ, Tan MW, Skelton N, Sandoval W, Sellers BD, Ciferri C, Smith PA, Reid PC, Cunningham CN, Rutherford ST, Payandeh J Nat Commun. 2024 Oct 8;15(1):8718. doi: 10.1038/s41467-024-52512-1. PMID:39379361^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.