We need more drugs for tuberculosis (TB), particularly multi-drug resistant (MDR) TB. TB treatment length (currently up to 24 months) needs to be shortened by using more effective drug combinations. Extensively-drug resistant Mycobacterium tuberculosis (M. tb) isolates are virtually untreatable with existing antimicrobials. Therefore, new structural classes of drugs, that have novel modes of action, are needed for the treatment of drug-resistant TB. Antimicrobial drug resistance in M. tuberculosis cannot be explained solely by the accumulation of resistance-conferring gene mutations; removal of drug through efflux pumps also have an important role to play. Clinical information indicates that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses during infection. In other bacteria, drug-efflux pumps are commonly controlled by repressors, known as TetR. Many of the drug-efflux pumps in the genome of M. tb are also associated with a TetR repressors. We hypothesise that in M. tb, efflux pumps have diverse roles in essential mechanisms such as cell wall processes/cell division and iron acquisition and that control of drug efflux is through transcriptional repression, mediated by the TetR family of transcriptional regulators. The aims of this PhD are to test these hypotheses and to characterise the function and the mechanisms that control drug efflux pumps in this deadly pathogen. Determining the primary function of efflux pumps and how they are regulated will provide novel targets for the discovery and development of new anti-mycobacterial drugs through our established network of academics, medicinal chemists, and Pharma.
Location
The PhD is a jointly supervised project between Dr Joanna Bacon at UKHSA and Dr Sharon Kendall at the Royal Veterinary College (RVC). The student will be registered at RVC and based for most of the time in the Drug Discovery Group at UKHSA Porton Down, Salisbury, Wiltshire, with short visits to RVC for academic activities and training in molecular techniques. In addition to project specific training the student will be able to make use of the skills development programme at the RVC and integrate with the multi-disciplinary Tuberculosis Research Group. Associate Supervisors at Kings College London (Prof Miraz Rahman) and Brighton and Sussex Medical School (Prof Simon Waddell) also offer opportunities to the student to engage with medicinal chemistry activities and cutting-edge transcriptomics, respectively. This project presents a unique opportunity to combine both academic and public sector experiences in a project to tackle a major global pathogen.
Funding
The project is funded by the UK Health Security Agency (UKHSA), an executive agency of the UK Department of Health and Social Care. The funding covers the tuition fees and provides an annual stipend for three years (currently at £18,062 for 2022-2023). See RVC Tuition Fee status for details of applicable fees.
Eligibility
We invite applications from candidates who hold/or expect to gain a first or upper second class honours degree (or equivalent), or an MSci or Master’s degree from a range of disciplines such as medicine, veterinary medicine, biological sciences, animal sciences, social sciences, statistics and economics. Candidates with a lower second-class degree supplemented by a Master’s qualification (in a relevant subject) will also be considered.
A good understanding of bacterial physiology and antimicrobial resistance, from University courses, is an essential requirement, as is an enthusiasm for TB research. Experience in some aspects of bacterial culture and antibiotic susceptibility assays is desirable as are skills in molecular biology, such as cloning, whole genome sequencing and/or RNA analyses and in silico analyses/bioinformatics. Knowledge of what is required to work within a CL-3 laboratory, will also be desirable.
Proposed start date: October 2022
Supervisor contact details: for informal enquiries about this PhD position please contact Dr Joanna Bacon E-mail: [Email Address Removed]
To apply for this PhD please send a CV and covering letter explaining your interest in the project via email to: [Email Address Removed]