| Structural highlights
Function
BAMD_ECOLI Part of the outer membrane protein assembly complex, which is involved in assembly and insertion of beta-barrel proteins into the outer membrane. Constitutes, with BamA, the core component of the assembly machinery. Probably involved in transient protein interactions.[HAMAP-Rule:MF_00922][1] [2] [3] [4] [5]
Publication Abstract from PubMed
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.
Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering.,Seyfert CE, Porten C, Yuan B, Deckarm S, Panter F, Bader CD, Coetzee J, Deschner F, Tehrani KHME, Higgins PG, Seifert H, Marlovits TC, Herrmann J, Muller R Angew Chem Int Ed Engl. 2023 Jan 9;62(2):e202214094. doi: 10.1002/anie.202214094. , Epub 2022 Dec 7. PMID:36308277[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Hagan CL, Kim S, Kahne D. Reconstitution of outer membrane protein assembly from purified components. Science. 2010 May 14;328(5980):890-2. doi: 10.1126/science.1188919. Epub 2010 Apr, 8. PMID:20378773 doi:10.1126/science.1188919
- ↑ Albrecht R, Zeth K. Structural basis of outer membrane protein biogenesis in bacteria. J Biol Chem. 2011 Aug 5;286(31):27792-803. Epub 2011 May 17. PMID:21586578 doi:10.1074/jbc.M111.238931
- ↑ Hagan CL, Kahne D. The reconstituted Escherichia coli Bam complex catalyzes multiple rounds of beta-barrel assembly. Biochemistry. 2011 Sep 6;50(35):7444-6. doi: 10.1021/bi2010784. Epub 2011 Aug 11. PMID:21823654 doi:10.1021/bi2010784
- ↑ Dong C, Hou HF, Yang X, Shen YQ, Dong YH. Structure of Escherichia coli BamD and its functional implications in outer membrane protein assembly. Acta Crystallogr D Biol Crystallogr. 2012 Feb;68(Pt 2):95-101. Epub 2012 Jan 6. PMID:22281737 doi:10.1107/S0907444911051031
- ↑ Seyfert CE, Porten C, Yuan B, Deckarm S, Panter F, Bader CD, Coetzee J, Deschner F, Tehrani KHME, Higgins PG, Seifert H, Marlovits TC, Herrmann J, Muller R. Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering. Angew Chem Int Ed Engl. 2023 Jan 9;62(2):e202214094. doi: 10.1002/anie.202214094. , Epub 2022 Dec 7. PMID:36308277 doi:http://dx.doi.org/10.1002/anie.202214094
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