PhD Studentship: Developing new therapies against the most dangerous antibiotic resistant bacteria

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

Research Theme: Infection, Immunity, Antimicrobial Resistance & Repair

Summary:  Antimicrobial resistance is an increasing societal issue, contributing to ~5,000,000 deaths in 2019. The highest priority bacteria are the ESKAPE pathogens that account for over half this mortality and morbidity. This project will contribute to fighting antimicrobial resistance by developing new high-throughput in vivo ESKAPE pathogen infection models in the wax moth Galleria mellonella. These will be used to test resistant clinical isolates with our novel compounds that make bacteria more susceptible to conventional antibiotics and facilitate further development of the compounds. The project will accelerate the development of our compounds and provide new in vivo models for antimicrobial discovery.

Project Description:

The so-called “ESKAPE pathogens” (Enterobacteria, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium) are the most serious antimicrobial resistant bacteria. In 2019, over 3,000,000 deaths worldwide were estimated to be associated with antimicrobial resistant strains of these bacteria alone.

The likely number of deaths will continue to increase without development of new treatment options and may make some existing medical procedures non-feasible. One approach that has been proposed is to develop potentiating medicines that weaken ancillary functions of specific bacteria, rendering them more susceptible to conventional antibiotics. The effectiveness of this approach needs to be demonstrated in a whole organism during the lead development/lead optimisation phase of drug discovery. This is particularly the case for academic projects as such drug development will not be fundable without these proof-of-concept data. The model organism Galleria mellonella has been used for over a decade as a model for infection.

Galleria larvae are cheap, have easy husbandry, and replicate results in the mouse well. Both acute and chronic infections can be modelled, and treatments can be delivered both prophylactically and post-infection. The Galleria Mellonella Research Centre at the University of Exeter has pioneered genetic engineering of Galleria. Importantly, this provides access to fluorescently labelled larvae. Combining these with labelling of bacteria allows highly effective detection of infection progression through imaging flow cytometry of larva haemolymph. However, this has only been demonstrated for infections of a small number of bacteria. We have developed compounds that inhibit the Macrophage Infectivity Potentiator (Mip) protein that is found in almost all infectious bacteria. Our compounds significantly potentiate standard of care antibiotics in mice against Klebsiella pneumoniae.

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