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Title | Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering. |
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Journal, issue, pages | Angew Chem Int Ed Engl, Vol. 62, Issue 2, Page e202214094, Year 2023 |
Publish date | Jan 9, 2023 |
Authors | Carsten E Seyfert / Christoph Porten / Biao Yuan / Selina Deckarm / Fabian Panter / Chantal D Bader / Janetta Coetzee / Felix Deschner / Kamaleddin H M E Tehrani / Paul G Higgins / Harald Seifert / Thomas C Marlovits / Jennifer Herrmann / Rolf Müller / |
PubMed 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 ...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. |
External links | Angew Chem Int Ed Engl / PubMed:36308277 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.0 - 3.4 Å |
Structure data | EMDB-15362, PDB-8adg: EMDB-15363, PDB-8adi: |
Source |
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Keywords | STRUCTURAL PROTEIN / BAM Complex; Darobactin 9 |