Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA‐Virus Inhibitors**

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.

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“…A family of cyclic thiazole- and thiazoline-rich non-ribosomal peptides, such as thiamyxin B 31 , have been isolated from the myxobacterial strain MCy9487 and have been found to have significant activity against RNA viruses. 29 Biosynthetic gene cluster analysis and feeding studies of isotopically labelled precursors have led to a proposed biosynthesis of the thiamyxins.…”

Genome-Guided Discovery of the Myxobacterial Thiolactone-Containing Sorangibactins

“…Detection was conducted by a diode array detector at 200−600 nm, the flow rate adjusted to 0.6 mL/min, the column heated to 45 °C, and the LC flow split to 75 μL/ min before entering the mass spectrometer. Following MS settings were applied for standard measurements: capillary voltage 4000 V, For the determination of stereocenters 7 and 12 of the Nmethylated thiazolidines as well as stereo center 4 of the cyclic homocysteine thiolactone moiety, an adapted Marfey's derivatization protocol already described for the thiamyxins 35 was applied after acidic hydrolysis to N-methyl cysteine and homocysteine, respectively.…”

“…Marfey's Analysis for the Determination of Stereochemistry. For the determination of stereocenters 7 and 12 of the Nmethylated thiazolidines as well as stereo center 4 of the cyclic homocysteine thiolactone moiety, an adapted Marfey's derivatization protocol already described for the thiamyxins 35 was applied after acidic hydrolysis to N-methyl cysteine and homocysteine, respectively.…”

Chromosomal organization of biosynthetic gene clusters suggests plasticity of myxobacterial specialized metabolism including descriptions for nine novel species:Archangium lansiniumsp. nov.,Myxococcus landrumussp. nov.,Nannocystis bainbridgeasp. nov.,Nannocystis poenicansasp. nov.,Nannocystis radixulmasp. nov.,Polyangium mundeleiniumsp. nov.,Pyxidicoccus parkwaysissp. nov.,Sorangium ateriumsp. nov.,Stigmatella ashevillenasp. nov

“…Although limited to metabolic profiles of axenically grown myxobacteria, this observation suggests investigation of lesser-studied genera within the phylum Myxococcota might increase the likelihood of metabolite discovery. Ongoing natural product discoveries from novel species of myxobacteria reinforce the need for continued isolation and characterization of environmental myxobacteria (6)(7)(8)(9). Most recently described Myxococcota belong to the genera Corallococcus, Myxococcus, and Pyxidicoccus (10)(11)(12)(13)(14), and comparatively fewer members of lesser-studied myxobacterial taxa have been reported over the last decade (15)(16)(17).…”