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Koller, T.O.* ; Scheid, U.* ; Kösel, T.* ; Herrmann, J.* ; Krug, D.* ; Boshoff, H.I.M.* ; Beckert, B.* ; Evans, J.C.* ; Schlemmer, J.* ; Sloan, B.* ; Weiner, D.M.* ; Via, L.E.* ; Moosa, A.* ; Ioerger, T.R.* ; Gräf, M.* ; Zinshteyn, B.* ; Abdelshahid, M.* ; Nguyen, F.* ; Arenz, S.* ; Gille, F.* ; Siebke, M. ; Seedorf, T.* ; Plettenburg, O. ; Green, R.* ; Warnke, A.-L. ; Ullrich, J.* ; Warrass, R.* ; Barry, C.E.* ; Warner, D.F.* ; Mizrahi, V.* ; Kirschning, A.* ; Wilson, D.N.* ; Müller, R.*

The myxobacterial antibiotic myxovalargin: Biosynthesis, structural revision, total synthesis and molecular characterization of ribosomal inhibition.

J. Am. Chem. Soc. 145, 851-863 (2023)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Beam-induced Motion; Cryo-em Structure; Antimicrobial Peptide; Mechanism; Discovery; Defocus; Family
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 0002-7863
e-ISSN 1520-5126
Journal Journal of the American Chemical Society
Quellenangaben Volume: 145, Issue: 2, Pages: 851-863 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Medicinal Chemistry (IMC)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-506300-001
Grants Bill and Melinda Gates Foundation
Deutsche Forschungsgemeinschaft (DFG)
MEYS CR
iNEXT
Intramural Research Program of NIAID/NIH
National Research Foundation of South Africa
South African Medical Research Council
Bill & Melinda Gates Foundation
DOI 10.1021/jacs.2c08816
WOS ID 000917124000001
Scopus ID 85146042328
PubMed ID 36603206
Erfassungsdatum 2023-01-11
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