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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



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