Trans‐Translation As A Target For Novel Antibiotics

Abstract

The trans‐translation pathway rescues ribosomes stalled at the end of mRNAs in bacteria. This pathway is required for viability or virulence in many species, but is not targeted by existing antibiotics. Using a high‐throughput screen, we identified compounds that inhibit trans‐translation but not protein synthesis. These compounds are not toxic to eukaryotic cells, but inhibit growth of a broad spectrum of bacterial species, including Staphylococcus aureus, Bacillus anthracis, Shigella flexneri, Mycobacterium tuberculosis, and Francisella tularensis, both in vitro and during ex vivo infection. Chemical cross‐linking was used to determine the molecular targets of these compounds in bacteria. One family of inhibitors was found to bind to the base of helix 89 in 23S rRNA, a site that is not bound by other antibiotics. These data validate trans‐translation as a target for antibiotic development and provide new insights into the early steps of ribosome rescue pathways.Support or Funding InformationThis work was supported by grants GM068720 and AI111692 from the National Institutes of Health.