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@ARTICLE{Seyfert:603154,
author = {Seyfert, Carsten E. and Müller, Alison V. and Walsh,
Danica J. and Birkelbach, Joy and Kany, Andreas M. and
Porten, Christoph and Yuan, Biao and Krug, Daniel and
Herrmann, Jennifer and Marlovits, Thomas and Hirsch, Anna K.
H. and Müller, Rolf},
title = {{N}ew {G}enetically {E}ngineered {D}erivatives of
{A}ntibacterial {D}arobactins {U}nderpin {T}heir {P}otential
for {A}ntibiotic {D}evelopment},
journal = {Journal of medicinal chemistry},
volume = {66},
number = {23},
issn = {0095-9065},
address = {Washington, DC},
publisher = {ACS},
reportid = {PUBDB-2024-00791},
pages = {16330 - 16341},
year = {2023},
note = {Helmholtz Validation Funds and Gottfried-Wilhem Leibniz
Preis der Deutschen Forschungsgemeinschaft (DFG) MU
1254/32-1 are acknowledged.},
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.},
cin = {CSSB-UKE-TM},
ddc = {610},
cid = {I:(DE-H253)CSSB-UKE-TM-20210520},
pnm = {633 - Life Sciences – Building Blocks of Life: Structure
and Function (POF4-633)},
pid = {G:(DE-HGF)POF4-633},
experiment = {EXP:(DE-MLZ)NOSPEC-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38093695},
UT = {WOS:001142969500001},
doi = {10.1021/acs.jmedchem.3c01660},
url = {https://bib-pubdb1.desy.de/record/603154},
}