About the Project
Pseudomonas aeruginosa is a bacterium commonly found in soil and water. However, it has become a World Health Organisation priority pathogen and a huge clinical challenge due to its ability to become an antibiotic-resistant superbug. Our previous work shows certain groups of P. aeruginosa are associated with environmental niches, while others are associated with the clinical niche. Essential to understanding antibiotic resistance is understanding the regulatory and metabolic changes that underlie the phenotype, and the evolutionary processes that result in them. We have shown that alterations in the gene for a global transcriptional regulator (mexT) and its repressor (mexS) lead to striking phenotypic and metabolic changes that can lead to either antibiotic resistant or sensitive phenotypes. Further, reversion to an antibiotic-sensitive phenotype appears to be associated with an increase in strain virulence. Currently, the impact of mutations in mexS alone on the broader phenotype of P. aeruginosa is unknown, and neither are the evolutionary trajectories that ‘environmental’ P. aeruginosa can take to adapt to clinical niches. This project aims to identify which lineages of P. aeruginosa are adapted to the clinical niche, how these differ from lineages that inhabit environmental niches, and the processes that govern the switch from environmental inhabitant to antibiotic-resistant pathogen.
This PhD project will combine basic microbiology, experimental evolution, genomics and bioinformatic analyses to identify biomarkers associated with different niches, determine the role of mexT and mexS in adaptation to the clinical environment, and characterise the trade-off between antibiotic resistance and virulence.
The student will be supervised by Dr Benjamin Evans (https://www.uea.ac.uk/medicine/people/profile/benjamin-evans#publicationsTab) in the Norwich Medical School UEA, and Prof John Wain (https://quadram.ac.uk/john-wain/) at the Quadram Institute. The student will benefit from regular interaction with world-leading experts in antibiotic resistance, bacterial adaptation, molecular diagnostics, and genome sequencing and analysis.
For more information on the supervisor for this project, please go here: https://people.uea.ac.uk/en/persons/benjamin-evans
The type of programme: PhD
The start date of the project: 01/10/2019
Mode of study: Full time
Entry requirements: Acceptable first degree in Biological sciences, microbiology, molecular biology, biomedical sciences, biochemistry, genetics, cell biology and minimum entry requirements is 2:1.
The standard minimum entry requirement for the studentship competition is 2:1 (or equivalent)
Funding Notes
This PhD project is in a Faculty of Medicine and Health Sciences competition for funded studentships. These studentships are funded for 3 years and comprise of Home/EU fees, a stipend of £15,009 and £1000 per annum to support research training. Overseas applicants may apply but are required to fund the difference between home/EU and overseas tuition fees (in 2019/20 the difference is £14,373 for lab based projects and £11,073 for non-lab based projects but fees are subject to an annual increase).
References
i) Olivares J, Alvarez-Ortega C, Linares JF, Rojo F, Köhler T, Martínez JL (2012). Overproduction of the multidrug efflux pump MexEF-OprN does not impair Pseudomonas aeruginosa fitness in competition tests, but produces specific changes in bacterial regulatory networks. Environ Microbiol, 14(8):1968-81. doi: 10.1111/j.1462-2920.2012.02727.x
ii) Kidd TJ, Ritchie SR, Ramsay KA, Grimwood K, Bell SC, Rainey PB. Pseudomonas aeruginosa exhibits frequent recombination, but only a limited association between genotype and ecological setting. PLoS ONE, 7(9): e44199. doi: 10.1371/journal.pone.0044199.
iii) Dotsch A, Schniederjans M, Khaledi A, Hornischer K, Schulz S, Bielecka A, Eckweiler D, Pohl S, Haussler S. The Pseudomonas aeruginosa transcriptional landscape is shaped by environmental heterogeneity and genetic variation. mBio, 6(4):e00749-15. doi: 10.1128/mBio.00749-15.
iv) D. Williams, J. L. Fothergill, B. Evans, J. Caples, S. Haldenby, M. J. Walshaw, M. A. Brockhurst, C. Winstanley & S. Paterson (2018). Transmission and lineage displacement drive rapid population genomic flux in cystic fibrosis airway infections of a Pseudomonas aeruginosa epidemic strain. Microbial Genomics, doi: 10.1099/mgen.0.000167.
v) D. Williams, B. A. Evans, S. Haldenby, M. J. Walshaw, M A. Brockhurst, C. Winstanley & S. Paterson (2015). Divergent, Coexisting Pseudomonas aeruginosa Lineages in Chronic Cystic Fibrosis Lung Infections. American Journal of Respiratory and Critical Care Medicine, 191(7); 775-785. doi: 10.1164/rccm.201409-1646OC.
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