Antimicrobial resistance (AMR) is a global challenge, and new therapeutics are essential in the fight against multidrug resistant bacteria. Pseudomonas aeruginosa (Pa) is a highly resistant pathogen, capable of causing a variety of infections, and has been identified by the World Health Organisation as one of the top three priority pathogens for new therapeutics.
Pa is a particular issue in chronic lung infections in conditions like cystic fibrosis (CF) and non-CF bronchiectasis. People with CF often suffer from these long term infections which require prolonged antimicrobial usage and the choice of antibiotics can become severely limited due to a combination of resistance and toxic side effects. The development of novel therapeutics is therefore crucial and non-traditional approaches such as anti-virulence therapeutics could provide expanded treatment options. Anti-virulence therapeutics are drugs that target key virulence factors. They do not kill bacteria but instead alter pathogenicity thereby making the infection less damaging to the host. This approach is therefore an attractive one and yet there are challenges to development.
Chronic Pa lung infections take place in a complex host and microbial environment that is challenging to replicate in in vitro models. This poses problems for screening novel antimicrobial agents, as results obtained in simple laboratory media are often not reflective of drug activity in vivo. The challenge is more complex still when it comes to screening of anti-virulence or adjuvant drugs, as standard microbiological endpoints that measure bacterial density or viability are often not appropriate and understanding host-pathogen interactions is key.
The studentship would be a collaboration between researchers at the University of Liverpool and the University of Sheffield, to develop new laboratory models, and adapt existing ones, for use to define the activity of anti-virulence drugs. Understanding and modelling the interplay between host and bacterial responses, using relevant preclinical models, is essential for successful development of anti-virulence strategies.
Project Approaches:
1. Quantification of key Pa virulence factors across a range of in vitro models, including artificial sputum, using molecular and phenotypic assays, to determine model suitability for study of virulence-associated targets.
2. Optimisation of an in vivo zebrafish model (including well-established CF models), as a tool to study Pa infection and clinically relevant host responses.
3. Utilisation of imaging techniques to study immune responses (neutrophil and macrophage dynamics) in in vitro and in vivo models, in the context of anti-virulence therapeutics.
This exciting project would provide training in Pa biology, in vitro and in vivo models, imaging and host-pathogen interactions, with the over-arching objective of determining the most appropriate models to test non-traditional, anti-virulence therapeutics, to accelerate their progression towards a clinical treatment option. The student will join a larger initiative (PIPE-CF) addressing the development pipeline for novel therapeutics in CF and link to a parallel CF Centre in Sheffield. We are looking for an enthusiastic student to join a friendly and dynamic group of researchers. The successful student will be well supported in the lab with a focus on publishing early as a stepping stone to future career success.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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