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@ARTICLE{Seyfert:486214,
author = {Seyfert, Carsten E and Porten, Christoph and Yuan, Biao and
Deckarm, Selina and Panter, Fabian and Bader, Chantal and
Coetzee, Janetta and Deschner, Felix and Tehrani, Kamaleddin
and Higgins, Paul G and Seifert, Harald and Marlovits,
Thomas and Herrmann, Jennifer and Müller, Rolf},
title = {{D}arobactins {E}xhibiting {S}uperior {A}ntibiotic
{A}ctivity by {C}ryo‐{EM} {S}tructure {G}uided
{B}iosynthetic {E}ngineering},
journal = {Angewandte Chemie / International edition},
volume = {62},
number = {2},
issn = {1433-7851},
address = {Weinheim},
publisher = {Wiley-VCH},
reportid = {PUBDB-2022-07156},
pages = {e202214094},
year = {2023},
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.},
cin = {FS-CS / CSSB-UKE-TM},
ddc = {540},
cid = {I:(DE-H253)FS-CS-20210408 /
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:36308277},
UT = {WOS:000893447000001},
doi = {10.1002/anie.202214094},
url = {https://bib-pubdb1.desy.de/record/486214},
}