Total synthesis and mechanism of action of the antibiotic armeniaspirol A

Nanaji Arisetti; Hazel L. S. Fuchs; Janetta Coetzee; Manuel Orozco; Dominik Ruppelt; Armin Bauer; Dominik Heimann; Eric Kuhnert; Satya P. Bhamidimarri; Jayesh A. Bafna; Bettina Hinkelmann; Konstantin Eckel; Stephan A. Sieber; Peter P. Müller; Jennifer Herrmann; Rolf Müller; Mathias Winterhalter; Claudia Steinem; Mark Brönstrup

doi:10.1039/D1SC04290D

Total synthesis and mechanism of action of the antibiotic armeniaspirol A†

Nanaji Arisetti,‡^ab Hazel L. S. Fuchs,

‡^a Janetta Coetzee,^bc Manuel Orozco,^c Dominik Ruppelt,^d Armin Bauer,

^e Dominik Heimann,

^a Eric Kuhnert,

^a Satya P. Bhamidimarri,^f Jayesh A. Bafna,^f Bettina Hinkelmann,^a Konstantin Eckel,

^g Stephan A. Sieber,

^gc Peter P. Müller,

^a Jennifer Herrmann,^bc Rolf Müller,

^bc Mathias Winterhalter,

^f Claudia Steinem

^dh and Mark Brönstrup

*^abi

Author affiliations

* Corresponding authors

^a Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany
E-mail: mark.broenstrup@helmholtz-hzi.de

^b German Centre for Infection Research, Partner Site Hannover-Braunschweig, Germany

^c Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus E8.1, 66123 Saarbrücken, Germany

^d Georg-August-Universität Göttingen, Institute of Organic and Biomolecular Chemistry, Tammannstraße 2, 37077 Göttingen, Germany

^e Sanofi R&D, Industriepark Höchst, 65926 Frankfurt, Germany

^f Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany

^g Department of Chemistry, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technische Universität München, Ernst-Otto-Fischer-Straße 8, 85748 Garching, Germany

^h Max-Planck-Institute for Dynamics and Self Organization, Am Faßberg 17, 37077 Göttingen, Germany

ⁱ Center for Biomolecular Drug Research (BMWZ), Leibniz Universität, 30159 Hannover, Germany

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.

Chemical Science

Total synthesis and mechanism of action of the antibiotic armeniaspirol A†

Abstract

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Total synthesis and mechanism of action of the antibiotic armeniaspirol A

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