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Tracking bacterial porin switching


Project Description

Antimicrobial resistance (AMR) is one of the major healthcare challenges of the 21st century. It has been estimated that AMR will lead to >10 million deaths per year and >100 trillion USD in lost economic output by 2050, if no immediate action is taken [1]. Identifying the molecular mechanisms through which bacteria become resistant to antibiotics is therefore a scientific and practical problem of great urgency and fundamental importance. In this multi-disciplinary project, you will develop novel chemical tools to address this problem.
THE PROJECT. In this project, you will elucidate the role of bacterial porins for the development of antimicrobial resistance in the bacterial pathogen Klebsiella pneumoniae. Klebsiella pneumoniae is the causative agent of pneumonia and a major nosocomial pathogen. It has considerable potential to spread multidrug resistance into the community and has recently been declared a “priority pathogen” by the World Health Organisation [2].

Porins are water-filled open channels in the outer membrane (OM) of Klebsiella pneumoniae and other Gram-negative bacteria, which allow the passive transport of small, hydrophilic molecules across the OM [3]. Porins are required for the acquisition of nutrients from the environment, and are essential for bacterial viability. Porins are also a major entry route for antibiotics.
Individual bacteria possess up to 8-10 different porin-encoding genes, whose expression is finely regulated in response to environmental factors, including antibiotics. Switching between different porins allows pathogens to modulate the permeability of their cell envelope. Porin switching has been linked to the stepwise increase in AMR [4], the progressive loss of efficacy of antibiotics, and the gradual increase in global resistance. The precise factors that drive porin switching, are, however, unknown. The identification of such factors is complicated by the ability of bacteria to rapidly alter their transcriptome in response to environmental changes.
IMPORTANCE. In this project, you will develop customized chemical tools – currently lacking – for the tracking of bacterial porins. You will use these tools to establish a detailed understanding of the factors that drive porin switching, and how this is linked to resistance development and bacterial pathogenicity in Klebsiella pneumoniae.

Training

This multidisciplinary project will provide in-depth training in a broad range of scientific techniques, including chemical tool development, bacterial cell culture, protein mass spectrometry, bacterial proteomics, containment microbiology, and analysis of multi-drug resistant clinical pathogens. It will give you exposure to different research environments at the chemistry/microbiology interface and provide an ideal opportunity for you to acquire transferable and generic skills such as time/project management and organisational skills, as well as experience in commercialization and science outreach. The project is particularly suited for a student with a background in chemistry, chemical biology, or a related subject, who wants to learn new skills in microbiology, proteomics and infectious disease research. Previous experience in organic synthesis is essential.

Research Environment

Your main base will be Britannia House, the new, dedicated chemistry facility at King’s College London. Here, you will have access to state-of-the-art laboratories and equipment for organic synthesis, chemical biology, non-pathogen microbiology, and bacterial proteomics. You will be trained in all relevant techniques, including the synthesis and characterisation of chemical probes, the preparation, handling and analysis of bacterial lysates, and the generation and interpretation of bacterial proteomics data.

Non-Academic Partner

The project will be carried out in collaboration with Public Health England (PHE) and co-supervised by Dr Matthew Wand in the Technology Development Group at PHE. You will benefit from at least one research placement per year at PHE, where you will be trained in a wide range of microbiological techniques, including advanced antibiotic susceptibility testing, observation of growth over time after challenge with antibiotics, synergy tests with antibiotic combinations, and the analysis of whole genome sequences, to understand the role of porin switching in the development of antimicrobial resistance.

Application Deadline

Applications must be complete, including both references, by 11th January 2019 at 5pm

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £16,777, plus an annual stipend enhancement of £2,000. Students from the EU are welcome to submit an application for funding, any offers will be subject to BBSRC approval and criteria.

References

O’Neill review on antimicrobial resistance: http://amr-review.org/
[2] WHO Global priority list of antibiotic resistant bacteria: https://tinyurl.com/y8cf9r2e
[3] Galdiero et al., Curr. Protein Pept. Sci. 2012, 13:843-854
[4] García-Sureda et al., Antimicrob. Agents Chemother. 2011, 55(10):4742-4747

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