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Discovery and biosynthesis of Gladiolin : a Burkholderia gladioli antibiotic with promising activity against Mycobacterium tuberculosis
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Song, Lijiang, Jenner, Matthew, Masschelein, Joleen, Jones, Cerith, Bull, Matthew J., Harris, Simon R., Hartkoorn, Ruben C., Vocat, Anthony, Romero-Canelón, Isolda, Coupland, Paul, Webster, Gordon, Dunn, Matthew, Weiser, Rebecca, Paisey, Christopher, Cole, Stewart T., Parkhill, Julian, Mahenthiralingam, Eshwar and Challis, Gregory L. (2017) Discovery and biosynthesis of Gladiolin : a Burkholderia gladioli antibiotic with promising activity against Mycobacterium tuberculosis. Journal of the American Chemical Society, 139 (23). pp. 7974-7981. doi:10.1021/jacs.7b03382 ISSN 0002-7863.
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Official URL: http://dx.doi.org/10.1021/jacs.7b03382
Abstract
An antimicrobial activity screen of Burkholderia gladioli BCC0238, a clinical isolate from a cystic fibrosis patient, led to the discovery of gladiolin, a novel macrolide antibiotic with potent activity against Mycobacterium tuberculosis H37Rv. Gladiolin is structurally related to etnangien, a highly unstable antibiotic from Sorangium cellulosum that is also active against Mycobacteria. Like etnangien, gladiolin was found to inhibit RNA polymerase, a validated drug target in M. tuberculosis. However, gladiolin lacks the highly labile hexaene moiety of etnangien and was thus found to possess significantly increased chemical stability. Moreover, gladiolin displayed low mammalian cytotoxicity and good activity against several M. tuberculosis clinical isolates, including four that are resistant to isoniazid and one that is resistant to both isoniazid and rifampicin. Overall, these data suggest that gladiolin may represent a useful starting point for the development of novel drugs to tackle multidrug-resistant tuberculosis. The B. gladioli BCC0238 genome was sequenced using Single Molecule Real Time (SMRT) technology. This resulted in four contiguous sequences: two large circular chromosomes and two smaller putative plasmids. Analysis of the chromosome sequences identified 49 putative specialized metabolite biosynthetic gene clusters. One such gene cluster, located on the smaller of the two chromosomes, encodes a trans-acyltransferase (trans-AT) polyketide synthase (PKS) multienzyme that was hypothesized to assemble gladiolin. Insertional inactivation of a gene in this cluster encoding one of the PKS subunits abrogated gladiolin production, confirming that the gene cluster is responsible for biosynthesis of the antibiotic. Comparison of the PKSs responsible for the assembly of gladiolin and etnangien showed that they possess a remarkably similar architecture, obfuscating the biosynthetic mechanisms responsible for most of the structural differences between the two metabolites.
Item Type: | Journal Article | ||||||||||||
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Subjects: | Q Science > QR Microbiology R Medicine > RC Internal medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||
Library of Congress Subject Headings (LCSH): | Multidrug-resistant tuberculosis -- Prevention | ||||||||||||
Journal or Publication Title: | Journal of the American Chemical Society | ||||||||||||
Publisher: | American Chemical Society | ||||||||||||
ISSN: | 0002-7863 | ||||||||||||
Official Date: | 14 June 2017 | ||||||||||||
Dates: |
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Volume: | 139 | ||||||||||||
Number: | 23 | ||||||||||||
Page Range: | pp. 7974-7981 | ||||||||||||
DOI: | 10.1021/jacs.7b03382 | ||||||||||||
Status: | Peer Reviewed | ||||||||||||
Publication Status: | Published | ||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||
Date of first compliant deposit: | 23 October 2017 | ||||||||||||
Date of first compliant Open Access: | 23 October 2017 | ||||||||||||
Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Welsh Assembly. Life Sciences Bridging Fund (WALSBF), Marie Curie Individual Fellowship | ||||||||||||
Grant number: | BB/L021692/1, BB/K002341/1 (BBSRC), LSBF R2-004 (WALSBF), Contract No. 656067 (Marie Curie Individual Fellowship) | ||||||||||||
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