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Titel: New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development
VerfasserIn: Seyfert, Carsten E.
Müller, Alison V.
Walsh, Danica J.
Birkelbach, Joy
Kany, Andreas M.
Porten, Christoph
Yuan, Biao
Krug, Daniel
Herrmann, Jennifer
Marlovits, Thomas C.
Hirsch, Anna
Müller, Rolf
Sprache: Englisch
Titel: Journal of medicinal chemistry
Bandnummer: 66
Heft: 23
Seiten: 16330-16341
Verlag/Plattform: ACS
Erscheinungsjahr: 2023
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Biosynthetic 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.
DOI der Erstveröffentlichung: 10.1021/acs.jmedchem.3c01660
URL der Erstveröffentlichung: https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01660
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-435895
hdl:20.500.11880/39057
http://dx.doi.org/10.22028/D291-43589
ISSN: 1520-4804
0022-2623
Datum des Eintrags: 28-Nov-2024
Fakultät: NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: NT - Pharmazie
Professur: NT - Prof. Dr. Anna Hirsch
NT - Prof. Dr. Rolf Müller
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes



Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons Creative Commons