TY - JOUR
T1 - Bioinformatic Expansion and Discovery of Thiopeptide Antibiotics
AU - Schwalen, Christopher J.
AU - Hudson, Graham A.
AU - Kille, Bryce
AU - Mitchell, Douglas A.
N1 - This work was supported in part by the National Institutes of Health (GM097142 and GM123998 to D.A.M.), the Chemistry-Biology Interface Training Program (GM070421 to C.J.S.), and the Seemon Pines Fellowship from the Department of Chemistry at the University of Illinois at Urbana-Champaign (to G.A.H.). We thank M. N. Goettge and W. W. Metcalf for the gift of microbiological materials and assistance and A. J. DiCaprio for NMR data acquisition.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Thiopeptides are members of the ribosomally synthesized and post-translationally modified peptide family of natural products. Most characterized thiopeptides display nanomolar potency toward Gram-positive bacteria by blocking protein translation with several being produced at the industrial scale for veterinary and livestock applications. Employing our custom bioinformatics program, RODEO, we expand the thiopeptide family of natural products by a factor of four. This effort revealed many new thiopeptide biosynthetic gene clusters with products predicted to be distinct from characterized thiopeptides and identified gene clusters for previously characterized molecules of unknown biosynthetic origin. To further validate our data set of predicted thiopeptide biosynthetic gene clusters, we isolated and characterized a structurally unique thiopeptide featuring a central piperidine and rare thioamide moiety. Termed saalfelduracin, this thiopeptide displayed potent antibiotic activity toward several drug-resistant Gram-positive pathogens. A combination of whole-genome sequencing, comparative genomics, and heterologous expression experiments confirmed that the thioamide moiety of saalfelduracin is installed post-translationally by the joint action of two proteins, TfuA and YcaO. These results reconcile the previously unknown origin of the thioamide in two long-known thiopeptides, thiopeptin and Sch 18640. Armed with these new insights into thiopeptide chemical-genomic space, we provide a roadmap for the discovery of additional members of this natural product family.
AB - Thiopeptides are members of the ribosomally synthesized and post-translationally modified peptide family of natural products. Most characterized thiopeptides display nanomolar potency toward Gram-positive bacteria by blocking protein translation with several being produced at the industrial scale for veterinary and livestock applications. Employing our custom bioinformatics program, RODEO, we expand the thiopeptide family of natural products by a factor of four. This effort revealed many new thiopeptide biosynthetic gene clusters with products predicted to be distinct from characterized thiopeptides and identified gene clusters for previously characterized molecules of unknown biosynthetic origin. To further validate our data set of predicted thiopeptide biosynthetic gene clusters, we isolated and characterized a structurally unique thiopeptide featuring a central piperidine and rare thioamide moiety. Termed saalfelduracin, this thiopeptide displayed potent antibiotic activity toward several drug-resistant Gram-positive pathogens. A combination of whole-genome sequencing, comparative genomics, and heterologous expression experiments confirmed that the thioamide moiety of saalfelduracin is installed post-translationally by the joint action of two proteins, TfuA and YcaO. These results reconcile the previously unknown origin of the thioamide in two long-known thiopeptides, thiopeptin and Sch 18640. Armed with these new insights into thiopeptide chemical-genomic space, we provide a roadmap for the discovery of additional members of this natural product family.
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U2 - 10.1021/jacs.8b03896
DO - 10.1021/jacs.8b03896
M3 - Article
C2 - 29983054
AN - SCOPUS:85049865883
SN - 0002-7863
VL - 140
SP - 9494
EP - 9501
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 30
ER -