Journal: Nat Microbiol / Year: 2022 Title: Computational identification of a systemic antibiotic for gram-negative bacteria. Authors: Ryan D Miller / Akira Iinishi / Seyed Majed Modaresi / Byung-Kuk Yoo / Thomas D Curtis / Patrick J Lariviere / Libang Liang / Sangkeun Son / Samantha Nicolau / Rachel Bargabos / Madeleine ...Authors: Ryan D Miller / Akira Iinishi / Seyed Majed Modaresi / Byung-Kuk Yoo / Thomas D Curtis / Patrick J Lariviere / Libang Liang / Sangkeun Son / Samantha Nicolau / Rachel Bargabos / Madeleine Morrissette / Michael F Gates / Norman Pitt / Roman P Jakob / Parthasarathi Rath / Timm Maier / Andrey G Malyutin / Jens T Kaiser / Samantha Niles / Blake Karavas / Meghan Ghiglieri / Sarah E J Bowman / Douglas C Rees / Sebastian Hiller / Kim Lewis / 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 ...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.
∠α: 90 ° / ∠β: 112 ° / ∠γ: 90 ° / A: 42.23 Å / B: 9.73 Å / C: 19.07 Å / Space group name: C2 / Space group num: 5
CTF correction
Type: NONE
3D reconstruction
Resolution: 1.05 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
Atomic model building
Protocol: AB INITIO MODEL / Space: RECIPROCAL
Refinement
Resolution: 1.05→9.5 Å / Cross valid method: NONE Details: Data was merged from 19 crystals of varying resolution limits up to 0.9A. Overall resolution limit was determined to be 1.05A and applied in the refinement program.
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