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

Abstract Four new PKS‐NRPS‐derived macrolide lactams with three unique ring fusion types were discovered from the Arctic sponge associated actinomycete Streptomyces somaliensis 1107 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 cluster sml consisting 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 compound 1 displayed 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 IC 50 values of 5.76 and 0.18 μM, respectively, and modulated the MAPK pathway. Moreover, compound 1 alleviated LPS‐induced systemic inflammation in our transgenic fluorescent zebrafish model.