Killing the unkillable. Developing bacterial capture compounds to identify new targets against antimicrobial resistant Staphylococcus aureus

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