Developing genetic and chemical tools for the GenoChemetic generation of natural product analogues
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Natural products provide one of the corner stones of both modern and historical medicine, contributing towards over 65 % of new FDA approved drugs that entered clinical trials between 1981 and 2014. It is partly down to the historic success of natural products in medicine that many people are once again looking to nature for a solution to the rise in antibiotic resistant bacterial infections. However, developing natural products towards clinical use poses a number of challenges. Notable examples of these challenges include the need to generate analogues of these compounds, which are oftentimes structurally complex, and the instability of many natural products. Within this work several approaches are set out to address these challenges, exploring novel genetic and complementary synthetic technologies, as well as looking towards natural solutions for sequestering and stabilising molecules. Chapters 2 – 5 explore tools towards the GenoChemetic generation of natural product analogues. Firstly the utilisation of alkyne tags in a GenoChemetic approach is explored. Chapter 2 first looks towards exploring the flexibility of a series of biosynthetic gene clusters to the uptake of alkyne containing starter units. Chapter 3 then generates genetic cassettes for the in situ biosynthesis of such starter units, for subsequent potential incorporation into natural products. A well utilised bioorthogonal handle within the group are aryl halides. Chapter 4 looks towards the genetic installation of such a handle onto natural products. Chapter 5 than goes on to explore work towards the development of a fluorogenic screening platform that could be used to screen for halogenase enzyme activity. Finally, in Chapter 6, a novel approach towards the photoprotection of polyene natural products is explored. Medicinally promising compounds that have poor photostability are often discounted from development. Here, Sporopollenin Exine Capsules (SpECs) are used to encapsulate the potent polyene antibiotic, marinomycin A, with a subsequent increase in its half-life under intense light from 95 s to over 7 hrs. This cheap, simple, and sustainable technology has the potential to provide a powerful new approach to drug stabilisation and delivery, as well as an exciting new tool for natural product extraction and purification.
Thesis, PhD Doctor of Philosophy
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/
Embargo Date: 2025-04-16
Embargo Reason: Thesis restricted in accordance with University regulations. Print and electronic copy restricted until 16th April 2025
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