Journal Article

Computational identification of a systemic antibiotic for Gram-negative bacteria

Nicolau, Samantha, Hiller, Sebastian, Liang, Libang, Son, Sangkeun, Maier, Timm, Malyutin, Andrey G., Jakob, Roman P., Morrissette, Madeleine, Karavas, Blake, Pitt, Norman, Iinishi, Akira, Curtis, Thomas D., Rath, Parthasarathi, Kaiser, Jens T., Modaresi, Seyed Majed, Ghiglieri, Meghan, Gates, Michael F., Rees, Douglas C., Yoo, Byung-Kuk, Miller, Ryan D., Bargabos, Rachel, Bowman, Sarah E. J., Lewis, Kim, Niles, Samantha, Lariviere, Patrick J.

2022

Overview

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. Computational search identifies dynobactin A which is a systemically active, natural-product peptide antibiotic that kills Gram-negative bacteria.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 101/58 / 101/6 / 631/114 / 631/154 / 631/326/22/1290 / 631/535/1258 / Animals / Anti-Bacterial Agents - metabolism / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacterial Outer Membrane Proteins - metabolism / Biomedical and Life Sciences / Computer applications / Crystal structure / Drug development / Escherichia coli - metabolism / Escherichia coli Proteins - genetics / Gram-negative bacteria / Gram-Negative Bacteria - metabolism / Infectious Diseases / Intestinal microflora / Life Sciences / Medical Microbiology / Mice / Microbiology / Microbiomes / Parasitology / Peptides / Peptides - metabolism / Phenylpropionates / Photorhabdus / Virology