8ADI

Cryo-EM structure of Darobactin 9 bound BAM complex

Summary for 8ADI

• Entry DOI: 10.2210/pdb8adi/pdb
• EMDB information: 15363
• Related PRD ID: PRD_002430
• Descriptor: Outer membrane protein assembly factor BamA, Outer membrane protein assembly factor BamB, Outer membrane protein assembly factor BamC, ... (6 entities in total)
• Functional Keywords: bam complex; darobactin 9, structural protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 6
• Total formula weight: 214349.35

Authors

Yuan, B.,Marlovits, T.C. (deposition date: 2022-07-08, release date: 2023-01-11, Last modification date: 2024-11-20)

Primary citation

Seyfert, C.E.,Porten, C.,Yuan, B.,Deckarm, S.,Panter, F.,Bader, C.D.,Coetzee, J.,Deschner, F.,Tehrani, K.H.M.E.,Higgins, P.G.,Seifert, H.,Marlovits, T.C.,Herrmann, J.,Muller, R.
Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering.
Angew.Chem.Int.Ed.Engl., 62:e202214094-e202214094, 2023

PubMed 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.

PubMed: 36308277
DOI: 10.1002/anie.202214094

Experimental method

ELECTRON MICROSCOPY (3.4 Å)