Isolation and Structural Elucidation of Armeniaspirols A-C: Potent Antibiotics against Gram-Positive Pathogens
| Autor: | Martin Gerlitz, Serge Sablé, Joachim Wink, Antje Nußer, Helene Olivan, Winfried Heyse, Herbert Kogler, Mark Brönstrup, Astrid Rey, Cedric Couturier, Luigi Toti, Michael Kurz, Armin Bauer, Cosima Dufour |
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| Rok vydání: | 2012 |
| Předmět: |
Staphylococcus aureus
medicine.drug_class Stereochemistry Antibiotics Crystallography X-Ray Gram-Positive Bacteria Catalysis chemistry.chemical_compound Biosynthesis In vivo Drug Discovery medicine Pyrroles Spiro Compounds Bacterial Structures Proline Biological Products Strain (chemistry) Chemistry Drug discovery Organic Chemistry General Chemistry Nuclear magnetic resonance spectroscopy Staphylococcal Infections In vitro Anti-Bacterial Agents |
| Zdroj: | Chemistry - A European Journal. 18:16123-16128 |
| ISSN: | 0947-6539 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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