TY  - JOUR
AU  - Seyfert, Carsten E.
AU  - Müller, Alison V.
AU  - Walsh, Danica J.
AU  - Birkelbach, Joy
AU  - Kany, Andreas M.
AU  - Porten, Christoph
AU  - Yuan, Biao
AU  - Krug, Daniel
AU  - Herrmann, Jennifer
AU  - Marlovits, Thomas
AU  - Hirsch, Anna K. H.
AU  - Müller, Rolf
TI  - New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development
JO  - Journal of medicinal chemistry
VL  - 66
IS  - 23
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - PUBDB-2024-00791
SP  - 16330 - 16341
PY  - 2023
N1  - Helmholtz Validation Funds and Gottfried-Wilhem Leibniz Preis der Deutschen Forschungsgemeinschaft (DFG) MU 1254/32-1 are acknowledged.
AB  - 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. 
LB  - PUB:(DE-HGF)16
C6  - pmid:38093695
UR  - <Go to ISI:>//WOS:001142969500001
DO  - DOI:10.1021/acs.jmedchem.3c01660
UR  - https://bib-pubdb1.desy.de/record/603154
ER  -