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Genome Editing Reveals Novel Thiotemplated Assembly of Polythioamide Antibiotics in Anaerobic Bacteria.
- Source :
-
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2018 Oct 22; Vol. 57 (43), pp. 14080-14084. Date of Electronic Publication: 2018 Oct 03. - Publication Year :
- 2018
-
Abstract
- Closthioamide (CTA) is a unique symmetric nonribosomal peptide with six thioamide moieties that is produced by the Gram-positive obligate anaerobe Ruminiclostridium cellulolyticum. CTA displays potent inhibitory activity against important clinical pathogens, making it a promising drug candidate. Yet, the biosynthesis of this DNA gyrase-targeting antibiotic has remained enigmatic. Using a combination of genome mining, genome editing (targeted group II intron, CRISPR/Cas9), and heterologous expression, we show that CTA biosynthesis involves specialized enzymes for starter unit biosynthesis, amide bond formation, thionation, and dimerization. Surprisingly, CTA biosynthesis involves a novel thiotemplated peptide assembly line that markedly differs from known nonribosomal peptide synthetases. These findings provide the first insights into the biosynthesis of thioamide-containing nonribosomal peptides and offer a starting point for the discovery of related natural products.<br /> (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Anti-Bacterial Agents pharmacology
Bacteria, Anaerobic genetics
CRISPR-Cas Systems
Carbon-13 Magnetic Resonance Spectroscopy
Chromatography, High Pressure Liquid
Clostridiales genetics
DNA Gyrase drug effects
Genes, Bacterial
Introns
Mass Spectrometry
Multigene Family
Peptide Synthases chemistry
Proton Magnetic Resonance Spectroscopy
Thioamides pharmacology
Anti-Bacterial Agents chemistry
Bacteria, Anaerobic chemistry
Clostridiales chemistry
Gene Editing
Thioamides chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3773
- Volume :
- 57
- Issue :
- 43
- Database :
- MEDLINE
- Journal :
- Angewandte Chemie (International ed. in English)
- Publication Type :
- Academic Journal
- Accession number :
- 30193003
- Full Text :
- https://doi.org/10.1002/anie.201807970