Spongisulfins A-C, three S-bridged angucycline dimers from Spongiactinospora rosea LHW63015 and their gut epithelium protective activity in Drosophila melanogaster

Abstract

Spongiactinospora rosea is a rare actinomycete derived from sponges belonging to the Streptosporangiaceae family. Genomic analysis of the strain S. rosea LHW63015 revealed that it contains 41 secondary metabolite biosynthetic gene clusters (BGCs), including four cryptic type II polyketide synthases (T2PKS) BGCs. By using a metabolite mining approach in conjunction with LC-MS guided isolation, we identified three previously undescribed sulfur-bridged angucycline dimers, namely spongisulfins A-C (1–3), a configurational isomeric new angucycline monomer, rubiginone A3 (4), as well as three known related analogs (5–7). Comprehensive analyses of 1D/2D NMR, HR-ESIMS, single-crystal X-ray diffraction and ECD calculations were performed to elucidate their structures. Further sequence analyses of the chain length factors (CLF) protein and biosynthetic gene clusters (BGCs) identified the angucycline-type T2PKS BGC spo in the genome. Additionally, a dextran sulfate sodium salt (DSS)-induced Drosophila melanogaster reporter line (gstd1-GFP) model was established to evaluate the gut epithelium protective activities of these isolated compounds. The results demonstrated that spongisulfin A (1), with a concentration of 5 nM, significantly alleviated the high mortality caused by 5 % DSS treatment, and exerted its gut protective activity by modulating the ROS level through alleviation the expression of gstd1 in the gut.

Keywords

• Spongiactinospora rosea
• Angucycline dimer
• Spongisulfins
• Biosynthetic gene cluster
• Drosophila melanogaster