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Identifying new drugs to combat the virulence mechanisms underlying multidrug-resistant typhoid.

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  • Full or part time
    Dr D Humphreys
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Multidrug-resistant typhoid
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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 and addressing unmet needs. 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.

’Developing a project to combat drug-resistant bacterial pathogens’
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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 (http://www.rnai.group.shef.ac.uk), 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 (collaborator Dr. Stephen Brown) 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 collaborator 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.

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit www.sheffield.ac.uk/sgs to learn more.

Funding Notes

Entry requirements
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD Studentship, you must complete the University's application form using the following link: http://www.sheffield.ac.uk/postgraduate/research/apply/applying

*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.

References

Humphreys, D*., Brooks, A.B.E*, Vikash, S., Arden, S., Buss, F., and Koronakis V. (2017). MYO6 is targeted by Salmonella virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells.
Proceedings of the National Academy of Sciences of the United States of America. 114 (15) 3915-3920. *co-first authors. PMID: 28348208

Humphreys D*. Singh V, Koronakis V*. (2016). Inhibition of WAVE Regulatory Complex activation by a bacterial virulence effector counteracts pathogen phagocytosis.
Cell Reports. 17 (3) 697-707. *co-corresponding authors. PMID: 27732847

Humphreys D, Davidson AC, Hume PJ, Koronakis V. (2012) Salmonella SopE and host GEF ARNO cooperate to recruit and activate WAVE to trigger bacterial invasion.
Cell Host & Microbe 11, 129-39. PMID: 22341462

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

Research output data provided by the Research Excellence Framework (REF)

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