Journal Article

PUBDB-2022-07156

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Darobactins Exhibiting Superior Antibiotic Activity by Cryo‐EM Structure Guided Biosynthetic Engineering

Seyfert, C. E. ; Porten, C. ; Yuan, B.CSSB* ; Deckarm, S. ; Panter, F. ; Bader, C. ; Coetzee, J. ; Deschner, F. ; Tehrani, K. ; Higgins, P. G. ; Seifert, H. ; Marlovits, T. (Corresponding author)CSSB*DESY* ; Herrmann, J. (Corresponding author) ; Müller, R. (Corresponding author)Extern*

2023
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/anie.202214094  doi:10.3204/PUBDB-2022-07156

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.

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Contributing Institute(s):

1. Strukturelle Mikrobiologie CSSB (FS-CS)
2. CSSB-UKE-TM (CSSB-UKE-TM)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)

Experiment(s):

1. No specific instrument

Appears in the scientific report 2023

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Database coverage:
; ; ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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