%0 Journal Article
%A Song, Lijiang
%A Jenner, Matthew
%A Masschelein, Joleen
%A Jones, Cerith
%A Bull, Matthew J.
%A R. Harris, Simon
%A Hartkoorn, Ruben C.
%A Vocat, Anthony
%A Romero-Canelon, Isolda
%A Coupland, Paul
%A Webster, Gordon
%A Dunn, Matthew
%A Weiser, Rebecca
%A Paisey, Christopher
%A Cole, Stewart T.
%A Parkhill, Julian
%A Mahenthiralingam, Eshwar
%A Challis, Gregory L.
%D 2017
%T Discovery
and Biosynthesis of Gladiolin: A Burkholderia gladioli Antibiotic with Promising Activity
against Mycobacterium tuberculosis
%U https://acs.figshare.com/articles/journal_contribution/Discovery_and_Biosynthesis_of_Gladiolin_A_i_Burkholderia_gladioli_i_Antibiotic_with_Promising_Activity_against_i_Mycobacterium_tuberculosis_i_/5077855
%R 10.1021/jacs.7b03382.s001
%2 https://ndownloader.figshare.com/files/8593558
%K antimicrobial activity screen
%K metabolite biosynthetic gene clusters
%K Mycobacterium tuberculosis H 37Rv Gladiolin
%K PKS
%K novel macrolide antibiotic
%K RNA
%K SMRT
%K gladioli BCC 0238 genome
%K etnangien
%K gladiolin
%K chromosome
%K gene cluster
%K Burkholderia gladioli Antibiotic
%X 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.
%I ACS Publications