The Myxobacterial Antibiotic Myxovalargin

Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

authored by

Timm O. Koller, Ullrich Scheid, Teresa Kösel, Jennifer Herrmann, Daniel Krug, Helena I.M. Boshoff, Bertrand Beckert, Joanna C. Evans, Jan Schlemmer, Becky Sloan, Danielle M. Weiner, Laura E. Via, Atica Moosa, Thomas R. Ioerger, Michael Graf, Boris Zinshteyn, Maha Abdelshahid, Fabian Nguyen, Stefan Arenz, Franziska Gille, Maik Siebke, Tim Seedorf, Oliver Plettenburg, Rachel Green, Anna Luisa Warnke, Joachim Ullrich, Ralf Warrass, Clifton E. Barry, Digby F. Warner, Valerie Mizrahi, Andreas Kirschning, Daniel N. Wilson, Rolf Müller

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.

Organisation(s)

Institute of Organic Chemistry

External Organisation(s)

Universität Hamburg
Saarland University
National Institutes of Health (NIH)
University of Cape Town (UCT)
Texas A and M University
Johns Hopkins University
Helmholtz Zentrum München - German Research Center for Environmental Health
Schering-Plough Biopharma

Type

Article

Journal

Journal of the American Chemical Society

Volume

145

Pages

851-863

No. of pages

13

ISSN

0002-7863

Publication date

18.01.2023

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Catalysis, General Chemistry, Biochemistry, Colloid and Surface Chemistry

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1021/jacs.2c08816 (Access: Open)