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Evolution of antimicrobial resistance within the human gut during antimicrobial therapy in preterm neonates S&T5

  • School: School of Science and Technology
  • Study mode(s): Full-time / Part-time
  • Starting: 2022
  • Funding: UK student / EU student (non-UK) / International student (non-EU) / Fully-funded

Overview

NTU's Fully-funded PhD Studentship Scheme 2022

Project ID: S&T5

Antimicrobial resistant infections threaten global health and new strategies are needed to slow the development of antimicrobial resistance (AMR). Bacteria acquire AMR through selection of mutations or via mobile genetic elements in the presence of an antimicrobial. To limit the development of AMR, and to ensure successful treatment of the infection, antibiotic therapy should be carefully tailored to each infection. This strategy is reliant on the accurately matching the AMR gene (genotype) with the expressed resistance to an antibiotic (phenotype). Studies of AMR evolution often use artificial growth media, laboratory-derived bacterial isolates, and non-clinically relevant antimicrobials. As both the environment and genetic background of bacteria are important for AMR development, translation of these studies to clinical practice is poor. Studying AMR development in models which closely mimic the human body would improve understanding of AMR evolution and translation.

Neonatal sepsis (NS) occurs in 1 in 700 live births and 1 in 6360 die, with preterm neonates one of the most vulnerable groups. While antibiotics used to treat NS will be active against the causative pathogen, they will also be active against the bacteria of the human microbiota, including in the gut. AMR mutations and sharing of plasmids within the bacterial community will be selected for during antibiotic therapy, potentially increasing the pool of antimicrobial resistant bacteria.

In this project we will use a novel evolutionary biology and genomics approach to produce clinically relevant data on AMR evolution. We will evaluate the use of a mini-gut organoid model grown from a preterm neonatal cell line to produce clinically relevant AMR mutations compared to nutrient-rich growth media. Using Escherichia coli isolates from human gut microbiota, we will select for AMR derivatives with resistance to antibiotics recommend for use in NS. These mutations will be identified using a bioinformatics approach and compared to E. coli isolates from the preterm microbiota.  Phenotypic characteristics of the AMR derivatives will be extensively studied, including effect on fitness, collateral susceptibility, and plasmid and phenotypic stability.

The outputs from this project will guide the design of antimicrobial regimens which will limit the emergence of AMR in E. coli. Additionally, a unique reference dataset of antimicrobial resistant mutations and the corresponding antimicrobial susceptibility profile (i.e. genotype-phenotype correlations) that arises in response to antimicrobial therapy will also be compiled. This will improve resistance prediction from genomic data, which is fundamental to rapid diagnostics to better inform treatment options.

Supervisory Team

Dr Alasdair Hubbard (Director of study, Nottingham Trent University)

Dr Christopher Stewart (Co-supervisor, Newcastle University)

Dr Maria Rosa Domingo-Sananes (Co-supervisor, Nottingham Trent University)

Professor Lesley Hoyles (Co-supervisor, Nottingham Trent University)

School strategic research priority

The  overall aim of this project aligns with NTU’s Health and Wellbeing research theme by influencing policy and healthcare management to improve the efficacy of antimicrobials. Our proposal also closely aligns with the Centre for Health, Ageing and Understanding Diseases’ research theme of Antimicrobial Resistance, Omics and Microbiota (AROM). It also aligns with NTU’s and the SST’s Strategic Research Vision and Plans by contributing to tackling the global challenge of antimicrobial resistance. Researchers in AROM try to understand how bacteria cause disease, how they become resistant to antibiotics and the role of the microbiome in human health. AROM research also has a particular focus on the development of novel antibiotics.

Entry qualifications

For the eligibility criteria, visit our studentship application page.

How to apply

For guidance and to make an application, please visit our studentship application page. The application deadline is Friday 14 January 2022.

Fees and funding

This is part of NTU's 2022 fully-funded PhD Studentship Scheme.

Guidance and support

Download our full applicant guidance notes for more information.

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