Microbial Natural Product Discovery through Nutritional and Epigenetic Manipulation

Aldholmi, Mohammed (2020) Microbial Natural Product Discovery through Nutritional and Epigenetic Manipulation. Doctoral thesis, University of East Anglia.

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Microbial natural products represent a significant portion of small-molecule drugs approved for clinical use, especially as anti-infective and anticancer agents. Nevertheless, most clinically used anti-infective and anticancer agents suffer from resistance and other drawbacks such as adverse effects, drug interactions and poor pharmacokinetic properties. Some of the main challenges in the natural product discovery field are the high rediscovery rates and low yield of natural products. One of the factors contributing to this problem is the fact that the genes responsible for the production of a great number of natural products are transcriptionally inactive (silent) or poorly expressed under laboratory conditions, resulting in undetectable concentrations of the corresponding products. Therefore, this project aimed at activating natural product genes in Euglena microalgae, Aspergillus fungi and actinomycete bacteria through nutritional and epigenetic manipulation.
Nutritional manipulation of Euglena resulted in the discovery of five novel natural products from E. gracilis, named euglenatides A-E, with moderate antifungal activity and potent antiproliferative activity. The investigation of other Euglena species revealed that euglenatide-related metabolites are produced by E. mutabilis and E. sanguinea. In Aspergillus fungi, nutritional manipulation led to significant changes in metabolite profiles leading to a substantial increase in the antimicrobial activity. Similarly, epigenetic manipulation led to a significant increase in the titre levels of phenylahistin in A. calidoustus and penicillic acid in A. westerdijkiae. Finally, nutritional manipulation in actinomycete bacteria led to higher yields of heronamides in Streptomyces sp. CMB-0406 while epigenetic manipulation did not display noticeable effects on the metabolite profile.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Nicola Veasy
Date Deposited: 17 Mar 2021 12:07
Last Modified: 17 Mar 2021 12:07
URI: https://ueaeprints.uea.ac.uk/id/eprint/79489


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