7r1w
E. coli BAM complex (BamABCDE) bound to dynobactin AE. coli BAM complex (BamABCDE) bound to dynobactin A
Structural highlights
FunctionBAMB_ECOLI Part of the outer membrane protein assembly complex, which is involved in assembly and insertion of beta-barrel proteins into the outer membrane. Nonessential member of the complex, which may orient the flexible periplasmic domain of BamA for interaction with other Bam components, chaperones and nascent outer membrane proteins.[1] [2] [3] [4] Publication Abstract from PubMedDiscovery of antibiotics acting against Gram-negative species is uniquely challenging due to their restrictive penetration barrier. BamA, which inserts proteins into the outer membrane, is an attractive target due to its surface location. Darobactins produced by Photorhabdus, a nematode gut microbiome symbiont, target BamA. We reasoned that a computational search for genes only distantly related to the darobactin operon may lead to novel compounds. Following this clue, we identified dynobactin A, a novel peptide antibiotic from Photorhabdus australis containing two unlinked rings. Dynobactin is structurally unrelated to darobactins, but also targets BamA. Based on a BamA-dynobactin co-crystal structure and a BAM-complex-dynobactin cryo-EM structure, we show that dynobactin binds to the BamA lateral gate, uniquely protruding into its beta-barrel lumen. Dynobactin showed efficacy in a mouse systemic Escherichia coli infection. This study demonstrates the utility of computational approaches to antibiotic discovery and suggests that dynobactin is a promising lead for drug development. Computational identification of a systemic antibiotic for gram-negative bacteria.,Miller RD, Iinishi A, Modaresi SM, Yoo BK, Curtis TD, Lariviere PJ, Liang L, Son S, Nicolau S, Bargabos R, Morrissette M, Gates MF, Pitt N, Jakob RP, Rath P, Maier T, Malyutin AG, Kaiser JT, Niles S, Karavas B, Ghiglieri M, Bowman SEJ, Rees DC, Hiller S, Lewis K Nat Microbiol. 2022 Oct;7(10):1661-1672. doi: 10.1038/s41564-022-01227-4. Epub , 2022 Sep 26. PMID:36163500[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||