Journal Article

A new antibiotic selectively kills Gram-negative pathogens

Manuse, Sylvie, Hiller, Sebastian, Imai, Yu, Mori, Miho, Honrao, Chandrashekhar, Makriyannis, Alexandros, Espinoza, Josh L., Savitski, Mikhail M., D’Onofrio, Anthony, Schäberle, Till F., Iinishi, Akira, Caboni, Mariaelena, Typas, Athanasios, Kaur, Hundeep, Noinaj, Nicholas, O’Rourke, Aubrie, Böhringer, Nils, Mateus, André, Ma, Xiaoyu, Guo, Jason J., Meyer, Kirsten J., Favre-Godal, Quentin, Ghiglieri, Meghan, Wuisan, Zerlina G., Nelson, Karen E., Lewis, Kim, Niles, Samantha, Green, Robert, Linares-Otoya, Luis, Wu, Runrun

2019

Overview

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens 1 , 2 . These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds 3 , 4 . As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s 2 . We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics. Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/6 / 14/28 / 14/34 / 14/63 / 140/131 / 38/22 / 38/23 / 38/39 / 38/70 / 38/77 / 38/91 / 631/154/555 / 631/326/22/1290 / 64/60 / 82/58 / 82/83 / 96/106 / Animals / Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - isolation & purification / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacterial Outer Membrane Proteins - antagonists & inhibitors / Bacterial Outer Membrane Proteins - chemistry / Bacterial Outer Membrane Proteins - genetics / Bacterial Outer Membrane Proteins - metabolism / Bacteriology / Cell Line / Disease Models, Animal / Drug Discovery / Drug resistance in microorganisms / Drug Resistance, Microbial - drug effects / Drug Resistance, Microbial - genetics / Escherichia coli Proteins - antagonists & inhibitors / Escherichia coli Proteins - chemistry / Escherichia coli Proteins - genetics / Escherichia coli Proteins - metabolism / Female / Gastrointestinal Microbiome - drug effects / Gram-negative bacteria / Gram-Negative Bacteria - drug effects / Gram-Negative Bacteria - genetics / Gram-Negative Bacteria - pathogenicity / Human health and pathology / Humanities and Social Sciences / Humans / Infectious diseases / Life Sciences / Methods / Mice / Microbial Sensitivity Tests / Microbial Viability - drug effects / Microbiology and Parasitology / Microbiota (Symbiotic organisms) / multidisciplinary / Mutation / Nematoda / Nematoda - microbiology / Operon - genetics / Pharmaceutical sciences / Pharmacology / Phenylpropionates - isolation & purification / Phenylpropionates - pharmacology / Photorhabdus - chemistry / Photorhabdus - genetics / Photorhabdus - isolation & purification / Physiological aspects / Properties / Science / Science (multidisciplinary) / Substrate Specificity / Symbiosis