The “superbug”, Methicillin resistant Staphylococcus aureus (MRSA) is a major threat to global health. Once inside a host, bacteria, like S. aureus, can sense external stresses such as nutrient deprivation, and activate defence strategies, which promote antimicrobial tolerance and drives chronic infections. The transition from colonisation to infection is exceptionally stressful for bacteria, as is treatment with antibiotics. One such defence network is controlled by two “alarmone” phospho-nucleotides, which signal this stress, regulating bacterial functions in ways that maximise survival. The two nucleotide alarmones are guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (ppGpp), which are produced specifically in response to stress and are responsible for coordinating cellular events that turn off growth and turn on genes for stress adaptation, antibiotic tolerance and survival. Whilst alarmone signalling has been linked to persistent and chronic infections, little is known about how they function to coordinate this adaptation on a molecular level. Our work aims to probe whether disruption of the (p)ppGpp signalling network could form the basis for the development of novel therapeutics.
Through our joint work in Microbiology and Chemistry, we are developing ppGpp-capture compounds as powerful tools to map this crucial signalling network. You will aid in the development of these tools and use them to probe new alarmone-protein interactions. Once identified you will define the mechanisms through which alarmone-protein interactions occur in the bacterial cell and crucially, the importance of these interactions for bacterial viability and resistance to antibiotics. Altogether, this project will define the mechanisms through which alarmones drive bacterial adaptation to stress, making major advances in our understanding of the superbug and help find new ways to treat it.
All the techniques and approaches are established in our groups. We provide training in writing, presenting and science outreach, as well as bench science and you will work in an exciting and thriving community of like-minded scientists in the Florey Institute (http://www.floreyinstitute.com/
). For more information on our work click on our lab pages (Rebecca Corrigan) (David Williams) or follow us on Twitter @corrigar1.
You should possess a high 2.1 or 1st class degree in microbiology, biochemistry or chemistry. Relevant laboratory experience is not required, but passion and enthusiasm for making a difference in the field of antimicrobial resistance is a must!
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 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 can be found on our website: http://www.dimen.org.uk/
1) Wood A, Irving SE, Bennison DJ & Corrigan RM (2019) The (p)ppGpp-binding GTPase Era promotes rRNA processing and cold adaptation in Staphylococcus aureus. PLoS Genetics 15(8):e1008346.
2) Corrigan RM, Bellows LE, Wood A & Grundling A (2016) ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria. PNAS 113(12):E1710-1719.
3) Wang B, Dai P, Ding D, Del Rosario A, Grant RA, Pentelute BL, Laub MT (2019) Affinity-based capture and identification of protein effectors of the growth regulator ppGpp. Nat Chem Biol 15(2):141-150.