A cyclopeptide and three oligomycin-class polyketides produced by an underexplored actinomycete of the genus <i>Pseudosporangium</i>

Abstract

Aside from the well-studied conventional actinomycetes such as Streptomyces , the less investigated genera of actinomycetes also represent a promising source of natural products. Genome mining indicated that members of the underexplored genus Pseudosporangium , from which no secondary metabolites have been reported to date, may harbor the biosynthetic machinery for the formation of novel natural products. The strain RD062863, that is available at a public culture collection, was obtained and subjected to metabolite analysis, which resulted in the discovery of a novel cyclopeptide, pseudosporamide ( 1 ), along with three new oligomycin-class polyketides, pseudosporamicins A–C ( 2 – 4 ). The unusual structure of compound 1 , featured by a biaryl-bond bridging across a tripeptide scaffold, N -acetyl-ʟ-Tyr-ʟ-Pro-ʟ-Trp, was determined by a combination of spectroscopic analyses, chemical derivatization, ECD calculation, and DFT-based theoretical chemical shift calculation, revealing the presence of an ( S a )-axial chirality around the biaryl bond. Compounds 2 – 4 lacked hydroxylation on the side chain of the spiroacetal rings, which showed clear contrast to other oligomycin congeners and related polyketides with ring-truncation or expansion. The new macrolides 2 – 4 displayed potent antimicrobial activity against the Gram-positive bacterium Kocuria rhizohpila and the plant pathogenic fungus Glomerella cingulata . All compounds showed moderate cytotoxicity against P388 murine leukemia cells with IC 50 values in the micromolar to submicromolar ranges. These results exemplified the validity of phylogeny-focused strain selection combined with biosynthetic gene-directed genome mining for the efficient discovery of new natural products.

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