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 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. The chemical structure and absolute stereochemistry of an unprecedented natural product family, the thiamyxins, is presented. These thiazole‐ and thiazoline‐containing cyclic depsipeptides are produced by a nonribosomal peptide synthetase‐polyketide synthase hybrid biosynthetic gene cluster, whose structure is described herein. The thiamyxins were found to exhibit promising antiviral activity against three different RNA viruses.