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Title: Elucidation of molecular mechanisms of antibiotics biosynthesis in Burkholderia gladioli
Author: Jian, Xinyun
ISNI:       0000 0004 7972 4086
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2018
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Burkholderia is a multi-talented genus of Gram-negative bacteria that has been recently shown to be a promising, untapped source of antibiotics with the potential to overcome antimicrobial resistance. An antimicrobial activity screen of a clinical isolate, B. gladioli BCC0238, identified a novel polyketide macrolide antibiotic, gladiolin, that is structurally related to a known antibiotic etnangien and exhibits potent activity against Mycobacterium tuberculosis. Gladiolin shows significantly increased stability towards light and air compared to etnangien, due to the absence of a highly unstable hexaene moiety present in the side chain of etnangien, which is the key structural difference between the two metabolites. Comparison of the polyketide synthases (PKSs) responsible for the biosynthesis of gladiolin and etnangien, however, reveals a strikingly similar domain architecture. This thesis reports the elucidation of the catalytic origins for the main structural differences between the two metabolites, revealing a trans-acting enoyl reduction event involved in shutting down a programmed iteration in gladiolin biosynthesis, which is proposed for the polyene formation in etnangien biosynthesis. In addition to gladiolin, a set of lipopeptodiolides, known as icosalides, which were originally reported as fungal metabolites, were also discovered from B. gladioli BCC0238. The non-ribosomal peptide synthase (NRPS) responsible for the biosynthesis of icosalides exhibits an unprecedented domain architecture revealing two directly adjacent condensation (C) domains embedded in the middle of the NRPS. In this study, the enzymology of these C domains has been investigated in vitro, elucidating an unusual double chain initiation mechanism for asymmetric peptidolide biosynthesis. Additionally, efforts towards in vitro reconstitution of the entire icosalide NRPS is reported, which may allow access to novel antibiotic analogues.
Supervisor: Not available Sponsor: China Scholarship Council ; University of Warwick
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry ; QR Microbiology