Details
| Original language | English |
|---|---|
| Pages (from-to) | 16023-16034 |
| Number of pages | 12 |
| Journal | Chemical science |
| Volume | 12 |
| Issue number | 48 |
| Early online date | 24 Nov 2021 |
| Publication status | Published - 28 Dec 2021 |
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.
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
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In: Chemical science, Vol. 12, No. 48, 28.12.2021, p. 16023-16034.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Total synthesis and mechanism of action of the antibiotic armeniaspirol A
AU - Arisetti, Nanaji
AU - Fuchs, Hazel L.S.
AU - Coetzee, Janetta
AU - Orozco, Manuel
AU - Ruppelt, Dominik
AU - Bauer, Armin
AU - Heimann, Dominik
AU - Kuhnert, Eric
AU - Bhamidimarri, Satya P.
AU - Bafna, Jayesh A.
AU - Hinkelmann, Bettina
AU - Eckel, Konstantin
AU - Sieber, Stephan A.
AU - Müller, Peter P.
AU - Herrmann, Jennifer
AU - Müller, Rolf
AU - Winterhalter, Mathias
AU - Steinem, Claudia
AU - Brönstrup, Mark
N1 - Funding Information: This work was co-funded by the German Centre for infection research (Grant no. TTU09.710), the Helmholtz International Lab for Anti-Infectives, and the President's Initiative and Network Fund of the Helmholtz Association of German Research Centres (HGF) under contract number VH-GS-202. Funding Information: We thank Dr Kirsten Harmrolfs, Ulrike Beutling and Wera Collisi for support with NMR measurements, mass spectrometry experiments and cellular assays, respectively. We would also like to thank Dr Ruben Hartkoorn from Institut Pasteur de Lille for providing pyrrolomycin-resistant mutant strains ofE. coli. The authors also thank Dr Nestor Zaburannyi for assistance with mutant genome analyses and Dr Chengzhang Fu for providing resistant mutants and knowledgeable insights.
PY - 2021/12/28
Y1 - 2021/12/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85121724471&partnerID=8YFLogxK
U2 - 10.1039/d1sc04290d
DO - 10.1039/d1sc04290d
M3 - Article
AN - SCOPUS:85121724471
VL - 12
SP - 16023
EP - 16034
JO - Chemical science
JF - Chemical science
SN - 2041-6520
IS - 48
ER -