Abstract
Two Burkholderia gladioli strains isolated from the lungs of cystic fibrosis patients were found to produce unusual lipodepsipeptides containing a unique citrate‐derived fatty acid and a rare dehydro‐β‐alanine residue. The gene cluster responsible for their biosynthesis was identified by bioinformatics and insertional mutagenesis. In‐frame deletions and enzyme activity assays were used to investigate the functions of several proteins encoded by the biosynthetic gene cluster, which was found in the genomes of about 45 % of B. gladioli isolates, suggesting that its metabolic products play an important role in the growth and/or survival of the species. The Chrome Azurol S assay indicated that these metabolites bind ferric iron, which suppresses their production when added to the growth medium. Moreover, a gene encoding a TonB‐dependent ferric‐siderophore receptor is adjacent to the biosynthetic genes, suggesting that these metabolites may function as siderophores in B. gladioli.
Highlights
Iron is an essential element for most organisms
Analysis of the B. gladioli BCC0238 complete genome sequence identified several gene clusters encoding cryptic nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS) and hybrid NRPS-PKS assembly lines.[12g]. Here we report the discovery of bolagladins A and B, novel lipodepsipeptides containing a unique citrate-derived fatty acid and a rare dehydro-b-alanine residue, as the metabolic products of one of these gene clusters
Using a combination of carbon source modification and inactivation of the biosynthetic pathway for gladiolin, which is produced at high titre and interferes with the detection of lower abundance metabolites, we have identified bolagladins A (1) and (2) as the metabolic product of a cryptic nonribosomal peptide biosynthetic gene cluster in B. gladioli
Summary
Iron is an essential element for most organisms. In biological systems, iron is mainly present in two oxidation states: ferrous and ferric.[1]. We have recently discovered that B. gladioli BCC0238, isolated from the sputum of a child with cystic fibrosis (CF), produces several specialised metabolites These include gladiolin, a novel macrolide with potent activity against drug resistant Mycobacterium tuberculosis clinical isolates,[12i] and icosalide A1,[17] an asymmetric lipopeptodiolide antibiotic originally isolated from an Aureobasidium species fungus,[18] but subsequently shown to be produced by various strains of B. gladioli including one associated with the fungus.[17,19] Analysis of the B. gladioli BCC0238 complete genome sequence identified several gene clusters encoding cryptic nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS) and hybrid NRPS-PKS assembly lines.[12g] Here we report the discovery of bolagladins A and B, novel lipodepsipeptides containing a unique citrate-derived fatty acid and a rare dehydro-b-alanine residue, as the metabolic products of one of these gene clusters. A combination of comparative bioinformatics analyses, targeted gene deletions, and enzyme activity assays elucidated several key steps in the biosynthesis of these unusual natural products, which we propose based on several lines of evidence may function as siderophores
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