title: Isolation and structural elucidation of armeniaspirols A-C: potent antibiotics against gram-positive pathogens.
abstract: 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.
authors.affiliation: Sanofi R&D, Department of Parallel Synthesis & Natural Products, Industriepark Hoechst, H823, 65926 Frankfurt, Germany.
authors.forename: Cosima
authors.initials: C
authors.lastname: Dufour
authors.forename: Joachim
authors.initials: J
authors.lastname: Wink
authors.forename: Michael
authors.initials: M
authors.lastname: Kurz
authors.forename: Herbert
authors.initials: H
authors.lastname: Kogler
authors.forename: Helene
authors.initials: H
authors.lastname: Olivan
authors.forename: Serge
authors.initials: S
authors.lastname: Sablé
authors.forename: Winfried
authors.initials: W
authors.lastname: Heyse
authors.forename: Martin
authors.initials: M
authors.lastname: Gerlitz
authors.forename: Luigi
authors.initials: L
authors.lastname: Toti
authors.forename: Antje
authors.initials: A
authors.lastname: Nußer
authors.forename: Astrid
authors.initials: A
authors.lastname: Rey
authors.forename: Cedric
authors.initials: C
authors.lastname: Couturier
authors.forename: Armin
authors.initials: A
authors.lastname: Bauer
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use*; D056226:Bacterial Structures; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006094:Gram-Positive Bacteria / Q000737:chemistry* / Q000187:drug effects*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000737:chemistry* / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D011758:Pyrroles; D013141:Spiro Compounds; C581180:armeniaspirol A; C581179:armeniaspirol B; C581181:armeniaspirol C