Discovery of Spiroketal Acids and Antarmycin Analogues from Deep-Sea Derived Pseudonocardia antarctica and Its ΔantB3 Mutant Strain

This study reports the discovery of eight new polyketide natural products from the deep-sea actinomycete Pseudonocardia antarctica SCSIO 07407 and its ΔantB3 mutant strain. Through OSMAC (One Strain Many Compounds)-based fermentation, six new spiroketal acid derivatives, namely, semiantarmycins B–G (1–6) and a spiroketal-polyketoester hybrid (7), were isolated from the wild-type strain. In parallel, a new antarmycin analogue, namely, antarmycin D (8), was obtained from the ΔantB3 mutant strain, in which the glycosyl 2,3-dehydratase encoding gene was disrupted. Structure elucidation using HR-ESIMS, 1D/2D NMR, and biosynthetic analysis revealed 1–3 feature a C-11 epimerized spiroketal core glycosylated with vancosamine or glucose, whereas 6 and 5 exhibit sequential dehydration and reduction at C-12/C-13. Compound 7 is the first reported spiroketal-polyketoester hybrid, and macrodiolide 8 incorporates rhamnose glycosylation along with C-11 methylation. Bioactivity screening revealed that 8 exhibits cytotoxicity against five cancer cell lines, including HCT116, SW480, MCF7, MDA-MB-468, and BT-549 with IC₅₀ values ranging from 2.02 to 7.65 μM. This work expands the chemical diversity of spiroketal acids and macrodiolides, highlighting deep-sea actinomycetes as an underexplored source of structurally unique and biologically active natural products.