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doi:10.22028/D291-44022
Titel: | The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition |
VerfasserIn: | Koller, Timm O. Scheid, Ullrich Kösel, Teresa Herrmann, Jennifer Krug, Daniel Boshoff, Helena I. M. Beckert, Bertrand Evans, Joanna C. Schlemmer, Jan Sloan, Becky Weiner, Danielle M. Via, Laura E. Moosa, Atica Ioerger, Thomas R. Graf, Michael Zinshteyn, Boris Abdelshahid, Maha Nguyen, Fabian Arenz, Stefan Gille, Franziska Siebke, Maik Seedorf, Tim Plettenburg, Oliver Green, Rachel Warnke, Anna-Luisa Ullrich, Joachim Warrass, Ralf Barry, Clifton E. Warner, Digby F. Mizrahi, Valerie Kirschning, Andreas Wilson, Daniel N. Müller, Rolf |
Sprache: | Englisch |
Titel: | Journal of the American Chemical Society : JACS |
Bandnummer: | 145 |
Heft: | 2 |
Seiten: | 851-863 |
Verlag/Plattform: | ACS |
Erscheinungsjahr: | 2023 |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent. |
DOI der Erstveröffentlichung: | 10.1021/jacs.2c08816 |
URL der Erstveröffentlichung: | https://pubs.acs.org/doi/10.1021/jacs.2c08816 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-440229 hdl:20.500.11880/39387 http://dx.doi.org/10.22028/D291-44022 |
ISSN: | 1520-5126 0002-7863 |
Datum des Eintrags: | 15-Jan-2025 |
Fakultät: | NT - Naturwissenschaftlich- Technische Fakultät |
Fachrichtung: | NT - Pharmazie |
Professur: | 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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koller-et-al-2023-the-myxobacterial-antibiotic-myxovalargin-biosynthesis-structural-revision-total-synthesis-and.pdf | 7,5 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons