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doi:10.22028/D291-43589
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 |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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seyfert-et-al-2023-new-genetically-engineered-derivatives-of-antibacterial-darobactins-underpin-their-potential-for.pdf | 6,64 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons