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000486214 1001_ $$aSeyfert, Carsten E$$b0
000486214 245__ $$aDarobactins Exhibiting Superior Antibiotic Activity by Cryo‐EM Structure Guided Biosynthetic Engineering
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000486214 520__ $$aOver 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.
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000486214 7001_ $$aPorten, Christoph$$b1
000486214 7001_ $$0P:(DE-H253)PIP1091457$$aYuan, Biao$$b2
000486214 7001_ $$aDeckarm, Selina$$b3
000486214 7001_ $$aPanter, Fabian$$b4
000486214 7001_ $$aBader, Chantal$$b5
000486214 7001_ $$aCoetzee, Janetta$$b6
000486214 7001_ $$aDeschner, Felix$$b7
000486214 7001_ $$aTehrani, Kamaleddin$$b8
000486214 7001_ $$aHiggins, Paul G$$b9
000486214 7001_ $$aSeifert, Harald$$b10
000486214 7001_ $$0P:(DE-H253)PIP1021412$$aMarlovits, Thomas$$b11$$eCorresponding author
000486214 7001_ $$0P:(DE-HGF)0$$aHerrmann, Jennifer$$b12$$eCorresponding author
000486214 7001_ $$0P:(DE-H253)PIP1094962$$aMüller, Rolf$$b13$$eCorresponding author
000486214 773__ $$0PERI:(DE-600)2011836-3$$a10.1002/anie.202214094$$gp. anie.202214094$$n2$$pe202214094$$tAngewandte Chemie / International edition$$v62$$x1433-7851$$y2023
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