Details
| Original language | English |
|---|---|
| Pages (from-to) | 851-863 |
| Number of pages | 13 |
| Journal | Journal of the American Chemical Society |
| Volume | 145 |
| Issue number | 2 |
| Early online date | 5 Jan 2023 |
| Publication status | Published - 18 Jan 2023 |
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.
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Chemical Engineering(all)
- Colloid and Surface Chemistry
Sustainable Development Goals
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In: Journal of the American Chemical Society, Vol. 145, No. 2, 18.01.2023, p. 851-863.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - The Myxobacterial Antibiotic Myxovalargin
T2 - Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition
AU - Koller, Timm O.
AU - Scheid, Ullrich
AU - Kösel, Teresa
AU - Herrmann, Jennifer
AU - Krug, Daniel
AU - Boshoff, Helena I.M.
AU - Beckert, Bertrand
AU - Evans, Joanna C.
AU - Schlemmer, Jan
AU - Sloan, Becky
AU - Weiner, Danielle M.
AU - Via, Laura E.
AU - Moosa, Atica
AU - Ioerger, Thomas R.
AU - Graf, Michael
AU - Zinshteyn, Boris
AU - Abdelshahid, Maha
AU - Nguyen, Fabian
AU - Arenz, Stefan
AU - Gille, Franziska
AU - Siebke, Maik
AU - Seedorf, Tim
AU - Plettenburg, Oliver
AU - Green, Rachel
AU - Warnke, Anna Luisa
AU - Ullrich, Joachim
AU - Warrass, Ralf
AU - Barry, Clifton E.
AU - Warner, Digby F.
AU - Mizrahi, Valerie
AU - Kirschning, Andreas
AU - Wilson, Daniel N.
AU - Müller, Rolf
N1 - Funding Information: This work was supported by grants from the Bill & Melinda Gates Foundation (subawards from OPP1024021 and OPP1158806 to V.M. and MULL17STB to R.M.), the South African Medical Research Council (to V.M.), the National Research Foundation of South Africa (to V.M.), and in part by the Intramural Research Program of NIAID/ NIH. We thank Ronnett Seldon and Audrey Jordaan for providing technical assistance. The authors thank Heinrich Steinmetz, Jutta Niggemann, Kathrin Wittstein, and Silke Reinecke of HZI for help with fermentation and compound purification. Furthermore, support from the team of Jörg Overmann at Leibniz-Institut DSMZ–Deutsche Sammlung von Mikroorganismen und Zellkulturen for genome sequencing and help by Nestor Zaburannyi for sequence assembly is acknowledged. Special thanks to Jiří Nováček (CEITEC MU) for cryo-EM data collection. Cryo-EM data was collected within the context of iNEXT (project number 7033 to D.N.W.) and the Horizon 2020 program of the European Union (CEITEC MU). The CIISB research infrastructure project LM2015043 funded by MEYS CR is gratefully acknowledged for the financial support of the measurements at the CF Cryo-electron Microscopy and Tomography CEITEC MU. This work has been supported by grants of the Deutsche Forschungsgemeinschaft (DFG) (WI3285/6-1 to D.N.W.).
PY - 2023/1/18
Y1 - 2023/1/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85146042328&partnerID=8YFLogxK
U2 - 10.1021/jacs.2c08816
DO - 10.1021/jacs.2c08816
M3 - Article
C2 - 36603206
AN - SCOPUS:85146042328
VL - 145
SP - 851
EP - 863
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 2
ER -