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Assessment of novel antimicrobials against foodborne bacteria using human intestinal organoids and systems biology (Schuller U20MEDSF)

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  • Full or part time
    Dr S Schüller
    Dr G Le Gall
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Antimicrobial resistance is a global health emergency causing at least 700,000 deaths each year due to drug-resistant infections. Therefore, new antibiotics are urgently needed. Transcription factor decoys (TFD) are a novel class of oligonucleotide antimicrobials which are delivered into bacterial cells via lipid nanoparticles and specifically target bacterial gene expression. One particular group of TFD has been shown to selectively reduce levels of the major foodborne pathogen E. coli in a mouse model.

The aim of this PhD project is to assess the efficacy of TFD on human E. coli infection using intestinal stem cell-derived organoids and determine the mechanism of TFD action by systems biology. This will be achieved by 1) establishing a human intestinal organoid model for E. coli infection, 2) evaluate the effect of TFD on E. coli survival and pathogenesis, drug penetration across the mucus layer and host cell cytotoxicity, and 3) unravel the mechanism of TFD action by transcriptomic and metabolomic analyses. Findings from this project will contribute to tackling the global problem of antimicrobial resistance by determining the efficacy and mechanism of action of a new class of oligonucleotide antimicrobials. In addition, it will provide a novel biologically relevant human in vitro system for evaluating future drug candidates against enteric pathogens.

The successful PhD student will receive expert training in a diverse and highly desirable range of relevant laboratory skills including work with bacterial pathogens, human intestinal organoid culture, confocal and scanning electron microscopy, cell and molecular biology (Schüller), metabolite extraction and mass spectrometry analysis (Le Gall), drug design and nanoparticle technology (McArthur).

For more information on the project’s supervisors, please visit:
https://people.uea.ac.uk/s_schuller
Type of programme: PhD
Start date of project: October 2020.
Mode of study: full time.
Studentship length: 3 years. (3 year studentships have a (non-funded) 1 year ‘registration only’ period).
Location: UEA: BCRE
Entry requirements:
a) acceptable first degree: Biological and Biomedical Sciences
b) The standard minimum entry requirement is 2:1

Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at http://www.uea.ac.uk/study/postgraduate/research-degrees/fees-and-funding.

A bench fee may also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project

References

1. Gonzalez-Paredes A, Sitia L, Ruyra A, Morris C, Wheeler GN, McArthur M, Gasco P (2019) Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides. Eur J Pharm Biopharm 134: 166-177.

2. Marín-Menéndez A, Montis C, Díaz-Calvo T, Carta D, Hatzixanthis K, Morris CJ, McArthur M, Berti D (2017) Antimicrobial Nanoplexes meet Model Bacterial Membranes: the key role of Cardiolipin. Sci Rep 7: 41242.

3. Ellis SJ, Yasir M, Browning DF, Busby SJW, Schüller S (2019) Oxygen and contact with human intestinal epithelium independently stimulate virulence gene expression in enteroaggregative Escherichia coli. Cell Microbiol 23: e13012.
4. Bryant WA, Stentz R, Le Gall G, Sternberg MJE, Carding SR and Wilhelm T (2017) In silico analysis of the small molecule content of outer membrane vesicles produced by Bacteroides thetaiotaomicron indicates an extensive metabolic link between microbe and host. Front Microbiol 8: 2440.



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