MRC DiMeN Doctoral Training Partnership: Identifying new drugs to combat the virulence mechanisms underlying multidrug-resistant typhoid

MULTIDRUG-RESISTANT TYPHOID
The world is facing an epidemic of multidrug-resistant (MDR) typhoid fever. This is exemplified by the H58 branch of drug-resistant Salmonella Typhi, which is spreading across Africa and Asia causing treatment failures and deadly outbreaks of typhoid in previously unaffected locations worldwide. In 2017, the WHO positioned drug-resistant Salmonella on the high priority list for antibiotic research and development. The repurposing of FDA-approved drugs to treat infectious diseases offers an attractive approach for accelerating development of new medicines. This PhD project aims to develop a high-throughput infection-based screen that will not only advance understanding of disease mechanisms but will identify novel anti-infectives, which have the potential to combat MDR typhoid and provide candidates for drug-repurposing.

A PHD PROJECT COMBATTING DRUG-RESISTANT BACTERIAL PATHOGENS.
The bacterial pathogen Salmonella Typhi causes typhoid by establishing intracellular human cell infections and inducing DNA damage through a unique virulence factor called the typhoid toxin. The major aim of the PhD project will be to develop a high-throughput infection approach that will enable two major virulence mechanisms to be assayed and targeted by a library of ~1250 FDA-approved drugs in combination: (i) the establishment of intracellular infections, and (ii) host cell DNA damage by the typhoid toxin.

By taking advantage of Molecular Devices ImageXpress high-content fluorescent microscopes at the Sheffield Drug and RNAi Screening Facilities, the student will engineer pathogens and develop innovative software algorithms to automate phenotyping during infection and identify novel anti-infectives. Building on the screen, the student will validate the drugs and elucidate where they act in the host-pathogen interaction to advance understanding of disease mechanisms. This will all be supported by expertise in host-pathogen interactions (primary supervisor Dr. Daniel Humphreys, https://www.sheffield.ac.uk/bms/research/humphreys) and high-throughput screening (second supervisor Dr. Stephen Brown, http://www.rnai.group.shef.ac.uk) at the Department of Biomedical Science, University of Sheffield.

The final phase of the project will move towards testing the candidate drugs on MDR Salmonella strains that are currently causing treatment failures and underlie MDR typhoid. This will be performed in collaboration with the third supervisor Professor Stephen Baker at the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam (https://www.ndm.ox.ac.uk/principal-investigators/researcher/stephen-baker). There will be opportunities to seek funded support for field work on MDR typhoid in Vietnam

Ultimately, this PhD project will exploit high-throughput and automated technologies to aid global efforts addressing the inexorable rise in antibiotic resistant bacteria and drug-resistant diseases.