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-Structure paper
タイトル | The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition. |
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ジャーナル・号・ページ | J Am Chem Soc, Vol. 145, Issue 2, Page 851-863, Year 2023 |
掲載日 | 2023年1月18日 |
![]() | 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 / ![]() ![]() ![]() |
PubMed 要旨 | 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 ...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 . 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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手法 | EM (単粒子) |
解像度 | 2.1 - 3.0 Å |
構造データ | EMDB-14121, PDB-7qq3: EMDB-15905, PDB-8b7y: |
化合物 | ![]() ChemComp-MG: ![]() ChemComp-ZN: ![]() ChemComp-HOH: ![]() ChemComp-FME: ![]() ChemComp-SPD: |
由来 |
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![]() | RIBOSOME / Antibiotic / Myxovalargin A / MyxA / Myxovalargin B / MyxB / fMet-tRNA / P-tRNA |