The Myxobacterial Antibiotic Myxovalargin: Biosynthesis,
Structural Revision, Total Synthesis, and Molecular
Characterization of Ribosomal Inhibition

J 2023

The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

KOLLER, Timm O, Ullrich SCHEID, Teresa KOESEL, Jennifer HERRMANN, Daniel KRUG et. al.

Basic information

Original name

The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

Authors

Edition

Journal of the American Chemical Society, WASHINGTON, AMER CHEMICAL SOC, 2023, 0002-7863

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10400 1.4 Chemical sciences

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 15.000 in 2022

DOI

http://dx.doi.org/10.1021/jacs.2c08816

UT WoS

000917124000001

Keywords in English

Mycobacterium tuberculosis; myxovalargin biosynthesis; cryo-EM structure; antibacterial

Abstract

V originále

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.

Links

90043, large research infrastructures

Name: CIISB

Citovat

KOLLER, Timm O, Ullrich SCHEID, Teresa KOESEL, 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 III BARRY, Digby F WARNER, Valerie MIZRAHI, Andreas KIRSCHNING, Daniel N WILSON and Rolf MUELLER. The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition. Journal of the American Chemical Society. WASHINGTON: AMER CHEMICAL SOC, 2023, vol. 145, No 2, p. 851–863. ISSN 0002-7863. Available from: https://dx.doi.org/10.1021/jacs.2c08816.

@article{2383477,
   author = {Koller, Timm O and Scheid, Ullrich and Koesel, Teresa and Herrmann, Jennifer and Krug, Daniel and Boshoff, Helena I M and Beckert, Bertrand and Evans, Joanna C and Schlemmer, Jan and Sloan, Becky and Weiner, Danielle M and Via, Laura E and Moosa, Atica and Ioerger, Thomas R and Graf, Michael and Zinshteyn, Boris and Abdelshahid, Maha and Nguyen, Fabian and Arenz, Stefan and Gille, Franziska and Siebke, Maik and Seedorf, Tim and Plettenburg, Oliver and Green, Rachel and Warnke, AnnaandLuisa and Ullrich, Joachim and Warrass, Ralf and Barry, Clifton E III and Warner, Digby F and Mizrahi, Valerie and Kirschning, Andreas and Wilson, Daniel N and Mueller, Rolf},
   article_location = {WASHINGTON},
   article_number = {2},
   doi = {http://dx.doi.org/10.1021/jacs.2c08816},
   keywords = {Mycobacterium tuberculosis; myxovalargin biosynthesis; cryo-EM structure; antibacterial},
   language = {eng},
   issn = {0002-7863},
   journal = {Journal of the American Chemical Society},
   title = {The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition},
   url = {https://pubs.acs.org/doi/10.1021/jacs.2c08816},
   volume = {145},
   year = {2023}
}

TY  - JOUR
ID  - 2383477
AU  - Koller, Timm O - Scheid, Ullrich - Koesel, Teresa - Herrmann, Jennifer - Krug, Daniel - Boshoff, Helena I M - Beckert, Bertrand - Evans, Joanna C - Schlemmer, Jan - Sloan, Becky - Weiner, Danielle M - Via, Laura E - Moosa, Atica - Ioerger, Thomas R - Graf, Michael - Zinshteyn, Boris - Abdelshahid, Maha - Nguyen, Fabian - Arenz, Stefan - Gille, Franziska - Siebke, Maik - Seedorf, Tim - Plettenburg, Oliver - Green, Rachel - Warnke, Anna-Luisa - Ullrich, Joachim - Warrass, Ralf - Barry, Clifton E III - Warner, Digby F - Mizrahi, Valerie - Kirschning, Andreas - Wilson, Daniel N - Mueller, Rolf
PY  - 2023
TI  - The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition
JF  - Journal of the American Chemical Society
VL  - 145
IS  - 2
SP  - 851–863
EP  - 851–863
PB  - AMER CHEMICAL SOC
SN  - 00027863
KW  - Mycobacterium tuberculosis
KW  - myxovalargin biosynthesis
KW  - cryo-EM structure
KW  - antibacterial
UR  - https://pubs.acs.org/doi/10.1021/jacs.2c08816
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.
ER  -

KOLLER, Timm O, Ullrich SCHEID, Teresa KOESEL, 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 III BARRY, Digby F WARNER, Valerie MIZRAHI, Andreas KIRSCHNING, Daniel N WILSON and Rolf MUELLER. The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition. \textit{Journal of the American Chemical Society}. WASHINGTON: AMER CHEMICAL SOC, 2023, vol.~145, No~2, p.~851–863. ISSN~0002-7863. Available from: https://dx.doi.org/10.1021/jacs.2c08816.

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