Premium
Isolation and Structural Elucidation of Armeniaspirols A–C: Potent Antibiotics against Gram‐Positive Pathogens
Author(s) -
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
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201201635
Subject(s) - antibiotics , microbiology and biotechnology , streptomyces , chemistry , vancomycin , in vivo , lead compound , bacteria , stereochemistry , in vitro , combinatorial chemistry , biology , staphylococcus aureus , biochemistry , genetics
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 armeniaspirol A–C ( 2 – 4 ), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non‐8‐ene scaffold. Labeling experiments with [1‐ 13 C] acetate, [1,2‐ 13 C2] acetate, and [U‐ 13 C] 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.