Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering

  • Carsten E Seyfert (Shared first author)
  • Christoph Porten (Shared first author)
  • Biao Yuan (Shared first author)
  • Selina Deckarm
  • Fabian Panter
  • Chantal Bader
  • Janetta Coetzee
  • Felix Deschner
  • Kamaleddin Tehrani
  • Paul G Higgins
  • Harald Seifert
  • Thomas Marlovits (Shared last author)
  • Jennifer Herrmann (Shared last author)
  • Rolf Müller (Shared last author)

Abstract

Over recent decades, the pipeline of antibiotics acting against Gram-negative bacteria is running dry, as most discovered candidate antibiotics suffer from insufficient potency, pharmacokinetic properties, or toxicity. The darobactins, a promising new small peptide class of drug candidates, bind to novel antibiotic target BamA, an outer membrane protein. Previously, we reported that biosynthetic engineering in a heterologous host generated novel darobactins with enhanced antibacterial activity. Here we utilize an optimized purification method and present cryo-EM structures of the Bam complex with darobactin 9 (D9), which served as a blueprint for the biotechnological generation of twenty new darobactins including halogenated analogs. The newly engineered darobactin 22 binds more tightly to BamA and outperforms the favorable activity profile of D9 against clinically relevant pathogens such as carbapenem-resistant Acinetobacter baumannii up to 32-fold, without observing toxic effects.

Bibliographical data

Original languageEnglish
ISSN1433-7851
DOIs
Publication statusPublished - 09.01.2023

Comment Deanary

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PubMed 36308277