Somalactams A–D: Anti‐inflammatory Macrolide Lactams with Unique Ring Systems from an Arctic Actinomycete Strain

• DOI: 10.1002/ange.202218085
• Publication Date: 2023-01-21T08:39:33Z
• Authors: Fan Yang; Moli Sang; Jing‐Rong Lu; Hui‐Min Zhao; Yike Zou; Wei Wu; Yong Yu; Ya‐Wei Liu; Wencheng Ma; Yun Zhang; Wei Zhang; Hou‐Wen Lin
• Keywords: Lipopolysaccharides; Lactams; Anti-Inflammatory Agents; 01 natural sciences; Anti-Bacterial Agents; 0104 chemical sciences; Multigene Family; Animals; Macrolides; Peptide Synthases; Polyketide Synthases; Zebrafish

AbstractFour new PKS‐NRPS‐derived macrolide lactams with three unique ring fusion types were discovered from the Arctic sponge associated actinomyceteStreptomyces somaliensis1107 using a genome mining strategy. Their structures were elucidated by a combination of MS, NMR spectroscopic analysis, and single‐crystal X‐ray diffraction. Biosynthetically, a novel gene clustersmlconsisting of three polyketide synthases and one hybrid polyketide synthase‐nonribosomal peptide synthetase together with cytochrome P450s and flavin‐containing monooxygenases and oxidoreductases was demonstrated to assemble the unique skeleton. Pharmacological studies revealed that compound1displayed a potent anti‐inflammatory effect without cytotoxicity. It inhibited IL‐6 and TNF‐α release in the serum of LPS‐stimulated RAW264.7 macrophage cells with IC50values of 5.76 and 0.18 μM, respectively, and modulated the MAPK pathway. Moreover, compound1alleviated LPS‐induced systemic inflammation in our transgenic fluorescent zebrafish model.