Developing nanoparticulate oligonucleotides as a target-specific antimicrobial for modulation of complex gut microbiota

Wong, Nichola (2018) Developing nanoparticulate oligonucleotides as a target-specific antimicrobial for modulation of complex gut microbiota. Doctoral thesis, University of East Anglia.

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Abstract

Developing nanoparticulate oligonucleotides as a target-specific antimicrobial for modulation of complex gut microbiota

The complex human gut microbiota harbours trillions of bacteria that are critical to health. Imbalances in the microbiota have been associated with conditions such as inflammatory bowel disease and metabolic disorder. Broad spectrum antibiotics that are used as therapy for bacterial infections cause major disruption to the diversity and structure of the gut microbiota, leading to dysbiosis.
For the advancement of microbiome-targeting, exploration of technologies that modulate the gut microbiota in a specific manner that minimise disruption to the gut microbiota is essential. In this thesis we examined a nucleic acid based-antimicrobial called Transcription Factor Decoys (TFDs), which are coupled with a proprietary nanoparticle for delivery to modulate the microbiota in a targeted manner. A TFD designed to target Enterobacteriaceae and delivered using nanoparticles was shown to enter the E. coli cells and inhibit bacterial growth. This system was also shown to work in a target-specific manner in an in vitro batch fermentation model of the human colon, and analysis by both culturing and 16S rRNA gene based metataxonomic analysis showed no major disruption to the rest of the gut microbiota. Metabonomic changes were evaluated to explore possible pathways involved for the TFD used to target Enterobacteriaceae. This TFD-specific antimicrobial activity against Enterobacteriaceae was also successfully translated to an in vivo mouse model with minimal changes to the gut microbiota.
The design of TFD targeting a phylogenetically diverse group with a similar metabolic function – sulphate reducing bacteria (SRB) – was also explored. Human SRB were isolated and a qPCR quantification method was designed. The work in this thesis serves as a proof-of-principle that TFD technology can specifically-target bacteria of interest and has the capability to selectively modulate the gut microbiota. This technology can potentially be developed to target other members of the gut microbiota to improve health status.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 19 Jul 2018 15:10
Last Modified: 01 Jun 2019 00:38
URI: https://ueaeprints.uea.ac.uk/id/eprint/67668
DOI:

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