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.

Flavin-Linked Oxidase Catalyzes Pyrrolizine Formation of Dichloropyrrole-Containing Polyketide Extender Unit in Chlorizidine A

“…Our proposed PKS incorporation of a dichloropyrrole-containing extender unit is unprecedented and extends CCR-based PKS building blocks into new chemical space that portends future polyketide bioengineering. Recently, the discovery of new pyrrolomycin derivatives 21 containing linear fatty acid substituents suggests a similar CCR-based biogenesis in their construction. The further post-PKS tailoring of prechlorizidine A’s acyl pyrrole side chain to form chlorizidine A’s pyrrolizine heterocycle not only reveals a new function for a flavin-dependent BBE, but also uniquely expands post-PKS tailoring reactions to include alkaloid synthesis.…”

Armeniaspirol Antibiotic Biosynthesis: Chlorination and Oxidative Dechlorination Steps Affording Spiro[4.4]non‐8‐ene

“…Armeniaspirols ( 1 – 3 ) are polyketide antibiotics produced by Streptomyces armeniacus DSM 19369 . They show potent activities at low‐microgram per mL minimum inhibitory concentrations (MICs) against multidrug‐resistant Gram‐positive bacterial pathogens such as methicillin‐resistant Staphylococcus aureus .…”

“…They show potent activities at low‐microgram per mL minimum inhibitory concentrations (MICs) against multidrug‐resistant Gram‐positive bacterial pathogens such as methicillin‐resistant Staphylococcus aureus . It was not possible to induce resistance to 1 by serial passaging, and 2 improved the survival rate of mice infected with MRSA, thus making armeniaspirols promising starting points for the development of new antibiotics …”

“…Armeniaspirols have unusual structural characteristics such as the unique spiro[4.4]non‐8‐ene moiety. Feeding studies demonstrated that all the carbons of the pyrrolinone moiety and the adjacent keto group of the benzofuranone ring are derived from proline . Acetate seems to be the origin for all carbons of the phenol ring and the side chain of 1 .…”

“…However, two structural features make 1 – 3 unique: the side chain of the resorcinol ring and the spiro[4.4]non‐8‐ene moiety. Feeding studies excluded the possibility that the side chains were incorporated by alkylation of the phenol ring . Potential bimolecular polyketide condensation proposals were made to explain this noncanonical polyketide biosynthesis .…”