Seyfert, Carsten E., Porten, Christoph ORCID: 0000-0002-7177-2783, Yuan, Biao ORCID: 0000-0002-7137-6270, Deckarm, Selina ORCID: 0000-0003-1678-8018, Panter, Fabian, Bader, Chantal D., Coetzee, Janetta, Deschner, Felix, Tehrani, Kamaleddin H. M. E., Higgins, Paul G., Seifert, Harald, Marlovits, Thomas C., Herrmann, Jennifer and Mueller, Rolf (2023). Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering. Angew. Chem.-Int. Edit., 62 (2). WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1521-3773

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Seyfert, Carsten E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Porten, ChristophUNSPECIFIEDorcid.org/0000-0002-7177-2783UNSPECIFIED
Yuan, BiaoUNSPECIFIEDorcid.org/0000-0002-7137-6270UNSPECIFIED
Deckarm, SelinaUNSPECIFIEDorcid.org/0000-0003-1678-8018UNSPECIFIED
Panter, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bader, Chantal D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coetzee, JanettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deschner, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tehrani, Kamaleddin H. M. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Higgins, Paul G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seifert, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marlovits, Thomas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-686822
DOI: 10.1002/anie.202214094
Journal or Publication Title: Angew. Chem.-Int. Edit.
Volume: 62
Number: 2
Date: 2023
Publisher: WILEY-V C H VERLAG GMBH
Place of Publication: WEINHEIM
ISSN: 1521-3773
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACINETOBACTER-BAUMANNII; RESISTANCE; EXPRESSION; LACTAMASE; DISCOVERYMultiple languages
Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68682

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