7T3H

MicroED structure of Dynobactin

7T3H の概要

• エントリーDOI: 10.2210/pdb7t3h/pdb
• 分子名称: TRP-ASN-SER-ASN-VAL-HIS-SER-TYR-ARG-PHE (2 entities in total)
• 機能のキーワード: antibiotics, drug development, natural product, bam a, microed, antibiotic
• 由来する生物種: Photorhabdus australis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 1311.40

構造登録者

Yoo, B.-K.,Kaiser, J.T.,Rees, D.C.,Miller, R.D.,Iinishi, A.,Lewis, K.,Bowman, S. (登録日: 2021-12-07, 公開日: 2022-10-19, 最終更新日: 2024-11-20)

主引用文献

Miller, R.D.,Iinishi, A.,Modaresi, S.M.,Yoo, B.K.,Curtis, T.D.,Lariviere, P.J.,Liang, L.,Son, S.,Nicolau, S.,Bargabos, R.,Morrissette, M.,Gates, M.F.,Pitt, N.,Jakob, R.P.,Rath, P.,Maier, T.,Malyutin, A.G.,Kaiser, J.T.,Niles, S.,Karavas, B.,Ghiglieri, M.,Bowman, S.E.J.,Rees, D.C.,Hiller, S.,Lewis, K.
Computational identification of a systemic antibiotic for gram-negative bacteria.
Nat Microbiol, 7:1661-1672, 2022

PubMed Abstract: Discovery 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 β-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.

PubMed: 36163500
DOI: 10.1038/s41564-022-01227-4

実験手法

ELECTRON CRYSTALLOGRAPHY (1.05 Å)