Journal Article

PUBDB-2024-00791

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development

Seyfert, C. E. ; Müller, A. V. ; Walsh, D. J. ; Birkelbach, J. ; Kany, A. M. ; Porten, C. ; Yuan, B.Extern*DESY* ; Krug, D. ; Herrmann, J. (Corresponding author) ; Marlovits, T. (Corresponding author)CSSB*DESY* ; Hirsch, A. K. H. ; Müller, R. (Corresponding author)

2023
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.3c01660  doi:10.3204/PUBDB-2024-00791

Abstract: Biosynthetic engineering of bicyclic darobactins, selectively sealing the lateral gate of the outer membrane protein BamA, leads to active analogues, which are up to 128-fold more potent against Gram-negative pathogens compared to native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising new antibiotic classes of the past decades. Here, we present a series of structure-driven biosynthetic modifications of our current frontrunner, darobactin 22 (D22), to investigate modifications at the understudied positions 2, 4, and 5 for their impact on bioactivity. Novel darobactins were found to be highly active against critical pathogens from the WHO priority list. Antibacterial activity data were corroborated by dissociation constants with BamA. The most active derivatives D22 and D69 were subjected to ADMET profiling, showing promising features. We further evaluated D22 and D69 for bioactivity against multidrug-resistant clinical isolates and found them to have strong activity.

Note: Helmholtz Validation Funds and Gottfried-Wilhem Leibniz Preis der Deutschen Forschungsgemeinschaft (DFG) MU 1254/32-1 are acknowledged.

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Contributing Institute(s):

1. 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

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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