Discovery and biosynthesis of gladiolin: a Burkholderia gladioli antibiotic with promising activity against Mycobacterium tuberculosis

Song, Lijiang, Jenner, Matthew, Masschelein, Joleen, Jones, Cerith ORCID: https://orcid.org/0000-0001-6275-0235, Bull, Matthew J., Harris, Simon R., Hartkoorn, Ruben C., Vocat, Anthony, Romero-Canelon, Isolda, Coupland, Paul, Webster, Gordon ORCID: https://orcid.org/0000-0002-9530-7835, Dunn, Matthew, Weiser, Rebecca ORCID: https://orcid.org/0000-0003-3983-3272, Paisey, Christopher, Cole, Stewart T., Parkhill, Julian, Mahenthiralingam, Eshwar ORCID: https://orcid.org/0000-0001-9014-3790 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. 10.1021/jacs.7b03382

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview

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:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QK Botany
Additional Information:	This is an open access article published under a Creative Commons Attribution (CC-BY) License.
Publisher:	American Chemical Society
ISSN:	0002-7863
Funders:	BBSRC
Date of First Compliant Deposit:	30 May 2017
Date of Acceptance:	22 May 2017
Last Modified:	15 Nov 2024 22:21
URI:	https://orca.cardiff.ac.uk/id/eprint/100965

Citation Data

Cited 54 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item