The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A90043%2F23%3A00140208" target="_blank" >RIV/00216224:90043/23:00140208 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/jacs.2c08816" target="_blank" >https://pubs.acs.org/doi/10.1021/jacs.2c08816</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/jacs.2c08816" target="_blank" >10.1021/jacs.2c08816</a>
Alternative languages
Result language
angličtina
Original language name
The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10400 - Chemical sciences
Result continuities
Project
—
Continuities
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Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of the American Chemical Society
ISSN
0002-7863
e-ISSN
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Volume of the periodical
145
Issue of the periodical within the volume
2
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
851-863
UT code for WoS article
000917124000001
EID of the result in the Scopus database
2-s2.0-85146042328