RESUMEN
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 armeniaspirolâ 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.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Productos Biológicos/química , Productos Biológicos/farmacología , Bacterias Grampositivas/química , Bacterias Grampositivas/efectos de los fármacos , Pirroles/química , Pirroles/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/química , Staphylococcus aureus/efectos de los fármacos , Estructuras Bacterianas , Cristalografía por Rayos X , Descubrimiento de DrogasRESUMEN
Armeniaspiroles, a novel class of natural products isolated from Streptomyces armeniacus, are characterized by a novel spiro[4.4]non-8-ene scaffold. Various derivatives of Armeniaspiroles could be obtained by halogenation, alkylation, addition/elimination or reductions. A total synthesis of the 5-chloro analog of Armeniaspirole A has been accomplished in a linear six-step sequence. 5-Chloro-Armeniaspirole A exhibits good activity against a range of multidrug-resistant, Gram-positive bacterial pathogens.