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Targeting membrane proteins as a novel strategy to combat antibiotic resistance in the hospital pathogen Pseudomonas aeruginosa S&T23

  • 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&T23

Pseudomonas aeruginosa is a significant cause of healthcare-associated infections with increasing resistance to conventional antibiotics. The World Health Organisation has listed P. aeruginosa as a pathogen of critical priority. Alternative antimicrobial strategies are sorely needed to combat this organism. One strategy is to target virulence factors to ‘disarm’ the pathogen and render it unable to cause disease. This project will focus on the role of membrane proteins involved in initiating infections and the development of novel antimicrobial compounds targeting these proteins.

The first of these is the Translocation and Assembly Module (TAM), a cell envelope complex that is composed of two proteins, an outer membrane beta-barrel protein TamA, and an inner membrane protein TamB. In E. coli, this complex is involved in the assembly of outer membrane components including autotransporters and pili, both of which are important classes of virulence factor, and further contributes to outer membrane integrity and antibiotic resistance in the healthcare-associated pathogen Klebsiella pneumoniae. In this part of the project, firstly deletion mutants of tamA and tamB will be made in P. aeruginosa, followed by proteomic profiling of the outer membranes of the mutants to see which factors are affected in P. aeruginosa. The effects of the gene deletions on virulence will be tested using a Galleria mellonella (wax moth) infection model. An assay will then be developed to allow drug screening for inhibitors of TAM function that could be useful new antimicrobials.

In parallel, magnesium import will be targeted for the development of novel antimicrobials. Magnesium is an essential nutrient that is available in limited amounts within the host. The magnesium transporter A (MgtA) is linked to survival and virulence in Salmonella; however, it is yet to be investigated in P. aeruginosa. MgtA acts as both a sensitive receptor and an uptake transporter of magnesium that is upregulated under limiting magnesium concentrations. The effects of deleting the mgtA gene on the growth and physiology of P. aeruginosa will be examined, focusing on the behaviour of the mutant under Mg2+ starvation conditions. In addition to classical microbiological techniques, global physiology will be evaluated using transcriptomics. As above, the mutants will be tested in the Galleria infection model and an in vitro assay will be set up that would allow for inhibitor screening. The in vitro drug screening part of the project will be done in collaboration with Prof. J. Preben Morth at the Technical University of Denmark.

School strategic research priority

This project is aligned with the research focus of the Antimicrobial Resistance, Omics and Microbiota (AROM) group, which includes investigating how bacteria cause disease and the development of novel antimicrobials. This project also aligns with research themes of the Centre for Health, Aging and Understanding Disease (CHAUD), which incorporates the AROM group.

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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