Issue 48, 2021

Total synthesis and mechanism of action of the antibiotic armeniaspirol A


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.

Graphical abstract: Total synthesis and mechanism of action of the antibiotic armeniaspirol A

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Article information

Article type
Edge Article
04 Aug 2021
24 Nov 2021
First published
24 Nov 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 16023-16034

Total synthesis and mechanism of action of the antibiotic armeniaspirol A

N. Arisetti, H. L. S. Fuchs, J. Coetzee, M. Orozco, D. Ruppelt, A. Bauer, D. Heimann, E. Kuhnert, S. P. Bhamidimarri, J. A. Bafna, B. Hinkelmann, K. Eckel, S. A. Sieber, P. P. Müller, J. Herrmann, R. Müller, M. Winterhalter, C. Steinem and M. Brönstrup, Chem. Sci., 2021, 12, 16023 DOI: 10.1039/D1SC04290D

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