Isolation and Structural Elucidation of ArmeniaspirolsA-C: Potent Antibiotics against Gram-Positive Pathogens

• Published in: Chemistry : a European journal 2012-12, Vol.18 (50), p.16123
• Main Authors: Dufour, Cosima, Wink, Joachim, Kurz, Michael, Kogler, Herbert, Olivan, Helene, Sablé, Serge, Heyse, Winfried, Gerlitz, Martin, Toti, Luigi, Nußer, Antje, Rey, Astrid, Couturier, Cedric, Bauer, Armin, Brönstrup, Mark
• Format: Article
• Language: English
• Subjects: Chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201201635

In an antibiotic lead discovery program, the known strain Streptomyces armeniacus DSM19369 has been found to produce three new natural products when cultivated on a malt-containing medium. The challenging structural elucidation of the isolated compounds was achieved by using three independent methods, that is, chemical degradation followed by NMR spectroscopy, a computer-assisted structure prediction algorithm, and X-ray crystallography. The compounds, named armeniaspirolA-C (2-4), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non-8-ene scaffold. Labeling experiments with [1-13C] acetate, [1,2-13C2] acetate, and [U-13C] proline suggest a biosynthesis through a rare two-chain mechanism. Armeniaspirols displayed moderate to high in vitro activities against Gram-positive pathogens such as methicillin-resistant S. aureus (MRSA) or vancomycin resistant E. faecium (VRE). As analogue 2 was active in vivo in an MRSA sepsis model, and showed no development of resistance in a serial passaging experiment, it represents a new antibiotic lead structure. [PUBLICATION ABSTRACT]