<jats:title>Abstract</jats:title><jats:p>In an antibiotic lead discovery program, the known strain <jats:italic>Streptomyces armeniacus</jats:italic> 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 (<jats:bold>2</jats:bold>–<jats:bold>4</jats:bold>), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non‐8‐ene scaffold. Labeling experiments with [1‐<jats:sup>13</jats:sup>C] acetate, [1,2‐<jats:sup>13</jats:sup>C2] acetate, and [U‐<jats:sup>13</jats:sup>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 <jats:italic>S. aureus</jats:italic> (MRSA) or vancomycin resistant <jats:italic>E. faecium</jats:italic> (VRE). As analogue <jats:bold>2</jats:bold> 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.