TY  - JOUR
AU  - Seyfert, Carsten E
AU  - Porten, Christoph
AU  - Yuan, Biao
AU  - Deckarm, Selina
AU  - Panter, Fabian
AU  - Bader, Chantal
AU  - Coetzee, Janetta
AU  - Deschner, Felix
AU  - Tehrani, Kamaleddin
AU  - Higgins, Paul G
AU  - Seifert, Harald
AU  - Marlovits, Thomas
AU  - Herrmann, Jennifer
AU  - Müller, Rolf
TI  - Darobactins Exhibiting Superior Antibiotic Activity by Cryo‐EM Structure Guided Biosynthetic Engineering
JO  - Angewandte Chemie / International edition
VL  - 62
IS  - 2
SN  - 1433-7851
CY  - Weinheim
PB  - Wiley-VCH
M1  - PUBDB-2022-07156
SP  - e202214094
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36308277
UR  - <Go to ISI:>//WOS:000893447000001
DO  - DOI:10.1002/anie.202214094
UR  - https://bib-pubdb1.desy.de/record/486214
ER  -