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A biosynthetic engineering approach to structural diversification of the enacyloxins
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Sargeant, Jacob R. (2021) A biosynthetic engineering approach to structural diversification of the enacyloxins. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3758624
Abstract
As anti-microbial resistance becomes increasingly concerning, it is imperative that drug discovery efforts are focussed on combatting it. Natural products have historically been crucial in the fight against pathogenic bacteria. However, their recent use has been in steady decline. An increased understanding of natural product biosynthesis presents an exciting opportunity to produce novel pharmaceuticals capable of tackling this growing threat. One such potential compound is the polyketide enacyloxin IIa, produced by Burkholderia ambifaria, which is active against the multi-drug resistant pathogen Acinetobacter baumannii.
Several approaches were used to produce analogues of enacyloxin IIa. Brominated analogues were generated by swapping all sources of chloride in the media with bromide, and analogues with modifications to the dihydroxycyclohexane carboxylic acid (DHCCA) moiety were generated by mutasynthesis. The possibility of using N-acetylcisteamine (NAC) thioester analogues as mimics of polyketide synthase linked intermediates was also investigated both in vivo and in vitro. The MIC of novel analogues against A. baumanii gave useful insights into the structure activity relationship (SAR) of enacyloxin with its microbial target, elongation factor Tu (EF-Tu).
Finally, via collaboration with Monash University and Nottingham University, a selection of analogues were used to investigate in vivo efficacy and toxicity in mouse models, and binding to EF-Tu using in-tact protein mass spectrometry, respectively.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology |
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Library of Congress Subject Headings (LCSH): | Drug resistance in microorganisms, Pathogenic bacteria, Polyketides, Biosynthesis | ||||
Official Date: | September 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: | Midlands Integrative Biosciences Training Partnership ; Biotechnology and Biological Sciences Research Council (Great Britain) | ||||
Format of File: | |||||
Extent: | xxv, 207 leaves : illustrations | ||||
Language: | eng |
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