Bioinformatic Expansion and Discovery of Thiopeptide Antibiotics

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 fo...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society Vol. 140; no. 30; pp. 9494 - 9501
Main Authors: Schwalen, Christopher J., Hudson, Graham A., Kille, Bryce, Mitchell, Douglas A.
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 01.08.2018
Subjects:
Actinobacteria - chemistry
Actinobacteria - genetics
Algorithms
Amino Acid Sequence
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - classification
Anti-Bacterial Agents - isolation & purification
Anti-Bacterial Agents - pharmacology
Bacillus subtilis - drug effects
Chemistry
Chemistry, Multidisciplinary
Computational Biology
Databases, Genetic
Enterococcus faecium - drug effects
Lyases - genetics
Markov Chains
Methicillin-Resistant Staphylococcus aureus - drug effects
Multigene Family
Peptides, Cyclic - classification
Peptides, Cyclic - genetics
Peptides, Cyclic - isolation & purification
Peptides, Cyclic - pharmacology
Physical Sciences
Protein Processing, Post-Translational
Science & Technology
Thioamides - chemistry
Whole Genome Sequencing
BERNINAMYCIN
COMPLEX
DATABASE
CLONING
BIOSYNTHESIS
COMPOUND
THIOSTREPTON
INHIBITOR
THIOVIRIDAMIDE
ATP
ISSN:0002-7863, 1520-5126, 1520-5126
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:NIH RePORTER
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.8b03896