Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering
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Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering. / Seyfert, Carsten E; Porten, Christoph; Yuan, Biao; Deckarm, Selina; Panter, Fabian; Bader, Chantal; Coetzee, Janetta; Deschner, Felix; Tehrani, Kamaleddin; Higgins, Paul G; Seifert, Harald; Marlovits, Thomas; Herrmann, Jennifer; Müller, Rolf.
in: ANGEW CHEM INT EDIT, Jahrgang 62, Nr. 2, 09.01.2023, S. e202214094.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering
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
N1 - © 2022 Wiley-VCH GmbH.
PY - 2023/1/9
Y1 - 2023/1/9
N2 - 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.
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.
U2 - 10.1002/anie.202214094
DO - 10.1002/anie.202214094
M3 - SCORING: Journal article
C2 - 36308277
VL - 62
SP - e202214094
JO - ANGEW CHEM INT EDIT
JF - ANGEW CHEM INT EDIT
SN - 1433-7851
IS - 2
ER -