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Triggering the expression of a silent gene cluster from genetically intractable bacteria results in scleric acid discovery

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Alberti, Fabrizio, Leng, Daniel J., Wilkening, Ina, Song, Lijiang, Tosin, Manuela and Corre, Christophe (2019) Triggering the expression of a silent gene cluster from genetically intractable bacteria results in scleric acid discovery. Chemical Science, 10 (2). pp. 453-463. doi:10.1039/C8SC03814G ISSN 2041-6520.

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Official URL: http://doi.org/10.1039/C8SC03814G

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Abstract

In this study, we report the rapid characterisation of a novel microbial natural product resulting from the rational derepression of a silent gene cluster. A conserved set of five regulatory genes was used as a query to search genomic databases and identify atypical biosynthetic gene clusters (BGCs). A 20-kb BGC from the genetically intractable Streptomyces sclerotialus bacterial strain was captured using yeast-based homologous recombination and introduced into validated heterologous hosts. CRISPR/Cas9-mediated genome editing was then employed to rationally inactivate the key transcriptional repressor and trigger production of an unprecedented class of hybrid natural products exemplified by (2-(benzoyloxy)acetyl)-L-proline, named scleric acid. Subsequent rounds of CRISPR/Cas9-mediated gene deletions afforded a selection of biosynthetic gene mutant strains which led to a plausible biosynthetic pathway for scleric acid assembly. Synthetic standards of scleric acid and a key biosynthetic intermediate were also prepared to confirm the chemical structures we proposed. The assembly of scleric acid involves two unique condensation reactions catalysed by a single NRPS module and an ATP-grasp enzyme that link a proline and a benzoyl residue to each end of a rare hydroxyethyl-ACP intermediate respectively. Scleric acid was shown to exhibit moderate inhibition activity against Mycobacterium tuberculosis, as well as inhibition of the cancer-associated metabolic enzyme Nicotinamide N-methyltransferase (NNMT).

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Natural products -- Synthesis, Pharmaceutical microbiology, Bioactive compounds, Gene editing, Gene expression, Antibiotics -- Development
Journal or Publication Title: Chemical Science
Publisher: Royal Society of Chemistry
ISSN: 2041-6520
Official Date: 14 January 2019
Dates:
DateEvent
14 January 2019Published
19 October 2018Available
11 October 2018Accepted
26 August 2018Submitted
Volume: 10
Number: 2
Page Range: pp. 453-463
DOI: 10.1039/C8SC03814G
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 23 October 2018
Date of first compliant Open Access: 23 October 2018
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
BB/M022765/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/M017982/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/M017982/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
UF090255[RS] Royal Societyhttp://dx.doi.org/10.13039/501100000288
EP/M027503/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
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