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 -