dc.identifier.uri |
http://dx.doi.org/10.15488/16564 |
|
dc.identifier.uri |
https://www.repo.uni-hannover.de/handle/123456789/16691 |
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dc.contributor.author |
Arisetti, Nanaji
|
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dc.contributor.author |
Fuchs, Hazel L. S.
|
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dc.contributor.author |
Coetzee, Janetta
|
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dc.contributor.author |
Orozco, Manuel
|
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dc.contributor.author |
Ruppelt, Dominik
|
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dc.contributor.author |
Bauer, Armin
|
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dc.contributor.author |
Heimann, Dominik
|
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dc.contributor.author |
Kuhnert, Eric
|
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dc.contributor.author |
Bhamidimarri, Satya P.
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dc.contributor.author |
Bafna, Jayesh A.
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dc.contributor.author |
Hinkelmann, Bettina
|
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dc.contributor.author |
Eckel, Konstantin
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dc.contributor.author |
Sieber, Stephan A.
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dc.contributor.author |
Müller, Peter P.
|
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dc.contributor.author |
Herrmann, Jennifer
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dc.contributor.author |
Müller, Rolf
|
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dc.contributor.author |
Winterhalter, Mathias
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dc.contributor.author |
Steinem, Claudia
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dc.contributor.author |
Brönstrup, Mark
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dc.date.accessioned |
2024-03-15T08:58:01Z |
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dc.date.available |
2024-03-15T08:58:01Z |
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dc.date.issued |
2021 |
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dc.identifier.citation |
Arisetti, N.; Fuchs, H.L.S.; Coetzee, J.; Orozco, M.; Ruppelt, D. et al.: Total synthesis and mechanism of action of the antibiotic armeniaspirol A. In: Chemical Science 12 (2021), Nr. 48, S. 16023-16034. DOI: https://doi.org/10.1039/d1sc04290d |
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dc.description.abstract |
Emerging antimicrobial resistance urges the discovery of antibiotics with unexplored, resistance-breaking mechanisms. Armeniaspirols represent a novel class of antibiotics with a unique spiro[4.4]non-8-ene scaffold and potent activities against Gram-positive pathogens. We report a concise total synthesis of (±) armeniaspirol A in six steps with a yield of 20.3% that includes the formation of the spirocycle through a copper-catalyzed radical cross-coupling reaction. In mechanistic biological experiments, armeniaspirol A exerted potent membrane depolarization, accounting for the pH-dependent antibiotic activity. Armeniaspirol A also disrupted the membrane potential and decreased oxygen consumption in mitochondria. In planar lipid bilayers and in unilamellar vesicles, armeniaspirol A transported protons across membranes in a protein-independent manner, demonstrating that armeniaspirol A acted as a protonophore. We provide evidence that this mechanism might account for the antibiotic activity of multiple chloropyrrole-containing natural products isolated from various origins that share a 4-acylphenol moiety coupled to chloropyrrole as a joint pharmacophore. We additionally describe an efflux-mediated mechanism of resistance against armeniaspirols. |
eng |
dc.language.iso |
eng |
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dc.publisher |
Cambridge : RSC |
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dc.relation.ispartofseries |
Chemical Science 12 (2021), Nr. 48 |
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dc.rights |
CC BY 3.0 Unported |
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dc.rights.uri |
https://creativecommons.org/licenses/by/3.0 |
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dc.subject |
Lipid bilayers |
eng |
dc.subject |
Synthesis (chemical) |
eng |
dc.subject |
Antibiotic activity |
eng |
dc.subject |
Antimicrobial resistances |
eng |
dc.subject |
Breakings |
eng |
dc.subject |
Chloropyrroles |
eng |
dc.subject |
Copper catalyzed |
eng |
dc.subject |
Gram-positive pathogens |
eng |
dc.subject |
Mechanism of action |
eng |
dc.subject |
Potent activity |
eng |
dc.subject |
Total mechanism |
eng |
dc.subject |
Total synthesis |
eng |
dc.subject |
Antibiotics |
eng |
dc.subject.ddc |
540 | Chemie
|
|
dc.title |
Total synthesis and mechanism of action of the antibiotic armeniaspirol A |
eng |
dc.type |
Article |
|
dc.type |
Text |
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dc.relation.essn |
2041-6539 |
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dc.relation.issn |
2041-6520 |
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dc.relation.doi |
https://doi.org/10.1039/d1sc04290d |
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dc.bibliographicCitation.issue |
48 |
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dc.bibliographicCitation.volume |
12 |
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dc.bibliographicCitation.firstPage |
16023 |
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dc.bibliographicCitation.lastPage |
16034 |
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dc.description.version |
publishedVersion |
eng |
tib.accessRights |
frei zug�nglich |
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