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Genetic interactions between mutations and horizontal gene transfer in the evolution of antimicrobial resistance S&T3

  • 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&T3

Antimicrobial resistance (AMR) is an increasingly important issue that threatens human health worldwide. The emergence and spread of resistance are notoriously difficult to predict, partly because it is affected by multiple factors. These include the rate and stability resistance gene acquisition by horizontal gene transfer (HGT), the rate of resistance-causing mutations, interactions between these genetic changes and the environment and interactions between different genetic changes or variants. We are particularly interested in such genetic interactions and the role they may have on the evolution of multi-drug resistance (simultaneous resistance to multiple antimicrobials). Genetic interactions can be epistatic (when a genetic change has different effects depending on other genetic variants in the cells) and/or pleiotropic (when a genetic effect has multiple phenotypic effects). Pleiotropic interactions of particular interest and importance in the evolution of AMR are the fitness costs of resistance and collateral susceptibility or resistance (when resistance to one antibiotic affects resistance to other antibiotics).

This project will focus on studying genetic interactions between horizontally transferred genes that confer AMR and mutations that confer AMR or alleviate the fitness costs of resistance. The initial aim will be to compare how resistance to an antibiotic evolves in cells that are already resistant to a different antibiotic, due to either chromosomal mutations or horizontally acquired genes. This comparison will show if acquisition of previous resistance through different mechanisms influences mutational pathways and the capacity for evolving resistance to more antibiotics. The bulk of the work will be carried out in Escherichia coli, one of the best characterised experimental models in molecular biology. E. coli is also member of the normal gut microbiota, although some strains can also cause serious infections. Evolved, resistant strains will be characterised in terms of antimicrobial susceptibility and fitness. Genetic changes that occur during evolution will be identified through whole-genome sequencing and causal changes validated by introducing them in ancestral strains. During the project, multiple antibiotics and mutations/genes/plasmids that confer AMR will be tested to infer comprehensive genetic interaction networks. Further work will involve validating the results in clinically relevant strains and comparison with genetic changes observed in databases. The outcome of this project will contribute to understanding the extent to which genetic interactions influence the evolution of AMR and may help to guide the design of better infection treatment regimens that prevent or slow down the evolution of multi-drug resistance.

School strategic research priority

This project aligns with the aims of the Centre for Health, Ageing and Understanding Disease (CHAUD) research theme of Antimicrobial Resistance, Omics and Microbiota (AROM). Our proposal falls within the Health and Wellbeing Strategic Theme by potentially impacting research into treatment practices and contribute to the sustainable use of antibiotics. 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.

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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