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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

Corresponding Author

Keywords Beam-induced Motion; Cryo-em Structure; Antimicrobial Peptide; Mechanism; Discovery; Defocus; Family

ISSN (print) / ISBN 0002-7863

e-ISSN 1520-5126

Journal Journal of the American Chemical Society

Quellenangaben Volume: 145, Issue: 2, Pages: 851-863

Publisher American Chemical Society (ACS)

Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Medicinal Chemistry (IMC)

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