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

01 September 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Antiviral agents
Natural products
Structure elucidation

Supplementary materials

Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA-Virus-Inhibitors - Supporting Information
We describe the microbiological and analytical methodology used for the preparation, analysis and purification of the Thiamyxins. We also report details on the bioinformatics analysis performed to investigate their biosynthetic origin, as well as NMR raw data and details about the biological assays.


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