A new antibiotic selectively kills Gram-negative pathogens

Nature. 2019 Dec;576(7787):459-464. doi: 10.1038/s41586-019-1791-1. Epub 2019 Nov 20.

Abstract

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds3,4. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s2. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / isolation & purification*
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Outer Membrane Proteins / antagonists & inhibitors
  • Bacterial Outer Membrane Proteins / chemistry
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / metabolism
  • Cell Line
  • Disease Models, Animal
  • Drug Discovery
  • 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 / drug effects*
  • Gram-Negative Bacteria / genetics
  • Gram-Negative Bacteria / pathogenicity*
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Microbial Viability / drug effects
  • Mutation
  • Nematoda / microbiology
  • Operon / genetics
  • Photorhabdus / chemistry
  • Photorhabdus / genetics
  • Photorhabdus / isolation & purification
  • Substrate Specificity
  • Symbiosis

Substances

  • Anti-Bacterial Agents
  • Bacterial Outer Membrane Proteins
  • BamA protein, E coli
  • Escherichia coli Proteins