Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA‐Virus Inhibitors**
Patrick A. Haack, Kirsten Harmrolfs, Chantal D. Bader, Ronald Garcia, Antonia P. Gunesch, Sibylle Haid, Alexander Popoff, Alexander Voltz, Heeyoung Kim, Ralf Bartenschlager, Thomas Pietschmann, Rolf Müller
Abstract
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 four congeners of this unprecedented natural product family with the non-cyclized thiamyxin D fused to a glycerol unit at the C-terminus. Alongside their structure elucidation, we present a concise biosynthesis model based on biosynthetic gene cluster analysis and isotopically labelled precursor feeding. We report incorporation of a 2-(hydroxymethyl)-4-methylpent-3-enoic acid moiety by a GCN5-related N-acetyltransferase-like decarboxylase domain featuring polyketide synthase. The thiamyxins show potent inhibition of RNA viruses 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 the potential for further development of the thiamyxins.