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Discovery and biosynthesis of gladiostatin : a novel glutarimide antibiotic from Burkholderia gladioli
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Nakou, Ioanna (2021) Discovery and biosynthesis of gladiostatin : a novel glutarimide antibiotic from Burkholderia gladioli. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3781290
Abstract
Bacteria belonging to the Burkholderia genus thrive in various ecological niches, ranging from the plant rhizosphere to the human lung, and play critical roles in ecological interactions often through the secretion of bioactive secondary metabolites. Genome mining and gene knockout experiments identified a trans-AT PKS in the B. gladioli BCC0238 and BCC1622 which is responsible for the biosynthesis of gladiostatin, a novel natural product that contains a glutarimide pharmacophore and a butenolide motif, moieties mainly appended in secondary metabolites of Streptomyces sp.. The biological activity of gladiostatin was investigated, showing a promising activity against several human cancer cell lines and inhibition towards tumor cell migration. The peculiarities found in PKS responsible for gladiostatin assembly were investigated through functional characterisation of key enzymes through in vitro biochemical assays and genetic engineering, indicating an unprecedented number of enoyl reduction events occurring in trans as well as a novel catalytic mechanism involved in the installation of the butenolide head.
The thesis describes a novel mechanism for megasynthase evolution which involves a recombination event in the middle of a catalytic domain. Using evolution’s point of recombination, a fully functional PKS was engineered in the lab as an optimally functioning PKS. The study provides new insights on evolutionary pathways of trans-AT PKS systems as well as a direction for efficient future diversity oriented biosynthesis of numerous polyketide compounds.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology R Medicine > RM Therapeutics. Pharmacology |
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Library of Congress Subject Headings (LCSH): | Burkholderiales, Gram-negative bacteria, Biosynthesis, Antibiotics -- Synthesis | ||||
Official Date: | October 2021 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Challis, Gregory L. | ||||
Sponsors: | Biotechnology and Biological Sciences Research Council (Great Britain) ; Midlands Integrative Biosciences Training Partnership | ||||
Format of File: | |||||
Extent: | xii, 238 leaves : illustrations | ||||
Language: | eng |
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