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Understanding the role of NAD(P)H quinone oxidoreductases in antibiotic resistance in Pseudomonas aeruginosa and other Gram-negative pathogens (REF: RDF22/HLS/APP/RYAN)


   Faculty of Health and Life Sciences

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  Dr Ali Ryan, Dr LG Dover  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Antimicrobial resistance (AMR) is one of the greatest challenges facing modern medicine. Amongst the pathogens of greatest concern are Gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Infection with antimicrobial resistant pathogens such as these leads to significantly longer hospital stays and increased mortality. Initially this project will focus on P. aeruginosa, a common nosocomial pathogen found in ICUs causing pneumonia and surgical site infections. Pseudomonas aeruginosa is also a significant cause of morbidity and mortality in patients suffering from cystic fibrosis where >80% adults suffering from the condition are chronically infected with the bacteria. In recent years multidrug resistant strains of P. aeruginosa are increasingly common many of which are resistant to frontline fluoroquinolone antibiotics (17% of clinical strains of P. aeruginosa tested in the US in 2018 were fluoroquinolone resistant).

NAD(P)H quinone oxidoreductases (NQOs) are a diverse family of flavoenzymes found in the cytosol of Gram-negative antimicrobial resistant pathogens such as P. aeruginosa. The reactions catalysed by NAD(P)H quinone oxidoreductases from P. aeruginosa have been extensively characterised. Recent studies using strains of P. aeruginosa lacking individual NQO genes have shown that NAD(P)H quinone oxidoreductases play an important role in both colonisation of mammalian hosts and in resistance to two classes of broad spectrum antibiotics used to treat bacterial infections (fluoroquinolones and aminoglycosides). These findings have been independently corroborated by genome wide association studies conducted in clinical strains of P. aeruginosa which identified mutations in NQO genes associated with fluoroquinolone resistance. Studies have also shown NAD(P)H quinone oxidoreductases are overexpressed in strains of Neisseria gonorrhoeae resistant to fluoroquinolones. The mechanism(s) underlying this role in antibiotic resistance remain unclear and will be the focus of this project. Pseudomonas aeruginosa strains carrying NQO gene knockouts show changes in a range of other pathogenic phenotypes including changes in motility, biofilm formation and virulence factor secretion, the mechanisms underlying which will also be investigated.

Working with our partners at the University of Oxford this project will focus initially on whether NAD(P)H quinone oxidoreductases are acting as cellular antioxidants, as treatment with fluoroquinolones is known to generate reactive oxygen species. To explain their other diverse roles in the cell we will determine whether, like NAD(P)H quinone oxidoreductases in eukaryotes, they regulate cellular processes by directly binding to and controlling the degradation of other proteins. Although some initial studies have identified protein binding partners of NAD(P)H quinone oxidoreductases in bacteria there has been no systematic investigation of whether these interactions play a role in regulating motility or other pathogenic phenotypes. Understanding the mechanism(s) underpinning the role of NAD(P)H quinone oxidoreductases in antibiotic resistance and pathogenic phenotypes will support development of inhibitors that can be co-administered with current antibiotics to allow for treatment of antimicrobial resistant strains of Gram-negative bacterial pathogens. 

Eligibility and How to Apply:

Please note eligibility requirement:

·      Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.

·      Appropriate IELTS score, if required.

·      Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere or if they have previously been awarded a PhD.

For further details of how to apply, entry requirements and the application form, see

https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/ 

Please note: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert). Applications that do not include the advert reference (e.g. RDF22/…) will not be considered.

Deadline for applications: 18 February 2022

Start Date: 1 October 2022

Northumbria University takes pride in, and values, the quality and diversity of our staff and students. We welcome applications from all members of the community.

Informal enquiries to Dr Ali Ryan ([Email Address Removed]).


Funding Notes

Each studentship supports a full stipend, paid for three years at RCUK rates (for 2021/22 full-time study this is £15,609 per year) and full tuition fees. UK and international (including EU) candidates may apply.
Studentships are available for applicants who wish to study on a part-time basis over 5 years (0.6 FTE, stipend £9,365 per year and full tuition fees) in combination with work or personal responsibilities.
Please also read the full funding notes (https://www.northumbria.ac.uk/research/postgraduate-research-degrees/studentships/rdf) which include advice for international and part-time applicants.

References

da Silva, RG; Karlyshev, A; Oldfield, N; Wooldridge, K; Bayliss, C; Ryan, A; Griffin, R; “Variant signal peptides of meningococcal vaccine antigen, FHbp, impairs processing affecting surface localisation and antibody-mediated killing” Front Microbiol 2019 DOI: 10.3389/fmicb.2019.02847
Crescente, V; Holland, S.M; Kashyap, S; Polycarpou, E; Sim, E; Ryan, A; “Identification of novel members of the bacterial azoreductase family in Pseudomonas aeruginosa” Biochem J 2016 (473) 549-558
Ryan, A; et al. “Identification of NAD(P)H quinone oxidoreductase activity in azoreductases from P. aeruginosa: azoreductases and NAD(P)H quinone oxidoreductases belong to the same FMN-dependent superfamily of enzymes” PloS One 2014 (9) e98551.
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