REL 2024-06-11 2025-07-08 2025-07-08 0000-0003-0145-4891 Timm Oliver Koller University of Hamburg Martin-Luther-King-Platz 6A Hamburg Hamburg Germany 20146 0000-0003-3816-3828 Daniel N Wilson University of Hamburg Martin-Luther-King-Platz 6A Hamburg Germany 20146 Koller TO Wilson DN German Research Foundation (DFG) WI3285/6-1 Germany 5.3 10.6019/EMPIAR-12403 EMDB molecule EMD-14121 EMD-15905 Koller TO Scheid U Kösel T Herrmann J Krug D Boshoff HIM Beckert B Evans JC Schlemmer J Sloan B Weiner DM Via LE Moosa A Ioerger TR Graf M Zinshteyn B Abdelshahid M Nguyen F Arenz S Gille F Siebke M Seedorf T Plettenburg O Green R Warnke AL Ullrich J Warrass R Barry CE Warner DF Mizrahi V Kirschning A Wilson DN Müller R Journal of the American Chemical Society J Am Chem Soc 2 145 851 863 2023 English 10.1021/jacs.2c08816 36603206

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.

EMPIAR-12111 Unaligned movies of cryo-EM data collection of antimicrobial peptide Myxovalaring B from Myxococcus fulvus bound to the 70S E.coli ribosome /data/stacks micrographs - multiframe MRC MRC 5132 20 32 BIT FLOAT 3838 1.053 3710 1.053

Unaligned movies of cryo-EM data collection of antimicrobial peptide Myxovalaring B from Myxococcus fulvus bound to the 70S E.coli ribosome