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000603154 1001_ $$0P:(DE-HGF)0$$aSeyfert, Carsten E.$$b0
000603154 245__ $$aNew Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development
000603154 260__ $$aWashington, DC$$bACS$$c2023
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000603154 500__ $$aHelmholtz Validation Funds and Gottfried-Wilhem Leibniz Preis der Deutschen Forschungsgemeinschaft (DFG) MU 1254/32-1 are acknowledged.
000603154 520__ $$aBiosynthetic engineering of bicyclic darobactins, selectively sealing the lateral gate of the outer membrane protein BamA, leads to active analogues, which are up to 128-fold more potent against Gram-negative pathogens compared to native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising new antibiotic classes of the past decades. Here, we present a series of structure-driven biosynthetic modifications of our current frontrunner, darobactin 22 (D22), to investigate modifications at the understudied positions 2, 4, and 5 for their impact on bioactivity. Novel darobactins were found to be highly active against critical pathogens from the WHO priority list. Antibacterial activity data were corroborated by dissociation constants with BamA. The most active derivatives D22 and D69 were subjected to ADMET profiling, showing promising features. We further evaluated D22 and D69 for bioactivity against multidrug-resistant clinical isolates and found them to have strong activity. 
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000603154 7001_ $$0P:(DE-HGF)0$$aMüller, Alison V.$$b1
000603154 7001_ $$0P:(DE-HGF)0$$aWalsh, Danica J.$$b2
000603154 7001_ $$0P:(DE-HGF)0$$aBirkelbach, Joy$$b3
000603154 7001_ $$0P:(DE-HGF)0$$aKany, Andreas M.$$b4
000603154 7001_ $$0P:(DE-HGF)0$$aPorten, Christoph$$b5
000603154 7001_ $$0P:(DE-H253)PIP1091457$$aYuan, Biao$$b6
000603154 7001_ $$0P:(DE-HGF)0$$aKrug, Daniel$$b7
000603154 7001_ $$0P:(DE-HGF)0$$aHerrmann, Jennifer$$b8$$eCorresponding author
000603154 7001_ $$0P:(DE-H253)PIP1021412$$aMarlovits, Thomas$$b9$$eCorresponding author
000603154 7001_ $$0P:(DE-HGF)0$$aHirsch, Anna K. H.$$b10
000603154 7001_ $$0P:(DE-HGF)0$$aMüller, Rolf$$b11$$eCorresponding author
000603154 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.3c01660$$gVol. 66, no. 23, p. 16330 - 16341$$n23$$p16330 - 16341$$tJournal of medicinal chemistry$$v66$$x0095-9065$$y2023
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