Bioinformatic Expansion and Discovery of Thiopeptide Antibiotics

• DOI: 10.1021/jacs.8b03896
• Publication Date: 2018-07-09T05:16:39Z
• Authors: Christopher J. Sc...; Graham A. Hudson; Bryce Kille; Douglas A. Mitchell
• Keywords: Thioamide; Moiety; Chemical space; Structural genomics; Natural product

Thiopeptides are members of the ribosomally synthesized and post-translationally modified peptide family natural products. Most characterized thiopeptides display nanomolar potency toward Gram-positive bacteria by blocking protein translation with several being produced at industrial scale for veterinary livestock applications. Employing our custom bioinformatics program, RODEO, we expand thiopeptide products a factor four. This effort revealed many new biosynthetic gene clusters predicted to be distinct from identified previously molecules unknown origin. To further validate data set clusters, isolated structurally unique featuring central piperidine rare thioamide moiety. Termed saalfelduracin, this displayed potent antibiotic activity drug-resistant pathogens. A combination whole-genome sequencing, comparative genomics, heterologous expression experiments confirmed that moiety saalfelduracin is installed joint action two proteins, TfuA YcaO. These results reconcile origin in long-known thiopeptides, thiopeptin Sch 18640. Armed these insights into chemical-genomic space, provide roadmap discovery additional product family.