Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA-Virus-Inhibitors

During our search for novel myxobacterial natural products, we discovered the Thiamyxins: thiazole- and thiazoline-rich non-ribosomal peptide-polyketide hybrids with potent antiviral activity. We isolated two cyclized and two open-chain congeners of this unprecedented natural product family, whereof the non-cyclized Thiamyxin D was found to be fused to a glycerol unit attached to the C-terminal carboxyl function. Alongside their structure elucidation and absolute stereochemistry, we present the biosynthetic origin of the Thiamyxins supported by a concise biosynthesis model based on biosynthetic gene cluster analysis and feeding experiments with isotope labelled precursors. We report an unprecedented incorporation of a 2-(hydroxymethyl)-4-methylpent-3-enoic acid moiety originating from the involved polyketide synthase featuring a rare GCN5-related N-acetyltransferase-like decarboxylase domain. The Thiamyxins showed potent inhibition of different RNA-viruses as analysed in cell culture models of corona, zika and dengue virus infection. Their potency up to a half maximal inhibitory concentration of 560 nM combined with milder cytotoxic effects on human cell lines indicate a potential for further development of the Thiamyxins as broad-spectrum antivirals targeting RNA-viruses.