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Molecular basis of antibiotic tolerance in Mycobacterium tuberculosis

  • Full or part time
  • Application Deadline
    Monday, April 01, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

A 3-year Department of Medicine PhD studentship is available to work in the laboratory of Dr Julien Vaubourgeix, in the MRC Centre for Molecular Bacteriology and Infection (CMBI) at Imperial College London. The successful applicant will be joining an internationally-renowned Research Centre, within one of the world’s top research universities.

Dr Vaubourgeix’s laboratory at the MRC-CMBI, Imperial College London, focuses on uncovering molecular mechanisms of antibiotic tolerance in mycobacteria–including the human pathogen Mycobacterium tuberculosis. Because antibiotic tolerance contributes to treatment length, treatment failure, disease recurrence, and the emergence of heritable drug resistance in tuberculosis, new drugs that preferentially target tolerant cells could improve outcomes. Research activities, including those that comprise this studentship, will contribute to our understanding of antibiotic tolerance in Mycobacterium tuberculosis to help build a foundation for the development of such drugs.

One branch of the Vaubougeix laboratory work focuses on elucidating the role of polyphosphate (poly(P)) in mycobacterial antibiotic tolerance. Poly(P)—the synthesis of which requires ATP—is a ubiquitous anionic polymer with diverse biological functions. In E. coli, poly(P) accumulates upon amino acid restriction and complexes with the Lon protease to mediate degradation of ribosomal proteins, which fuels a response to stress. Additionally, a mutant defective in poly(P) metabolism grown to stationary phase fails to form persisters at a wild-type level when exposed to ciprofloxacin, a gyrase inhibitor. In mycobacteria, strains of Mtb defective in poly(P) metabolism display altered susceptibility to drugs by mechanisms that remain elusive.

Preliminary studies revealed that poly(P) may serve as a molecular switch that controls entry into and exit from an antibiotic-tolerant state. The goal of this studentship will be to evaluate the molecular mechanisms by which stressed Mtb transiently redirects its ATP pool into poly(P) to drive the cell into an antibiotic-tolerant state through transcriptional and metabolic reprogramming. Another complementary goal will be to test if polyphosphate—which is a high-energy polymer—also mediates Mtb’s exit from stressed states.

Candidates will use numerous methodologies, spanning microbiology, genetics, biochemistry, mass-spectrometry and photomicroscopy. Prior experience is desirable but not essential. Candidates must be expected to have a first class or upper second class Honours degree and preferably a Master’s degree passed with merit or distinction. Only UK or EU nationals are eligible.

Funding Notes

The 3-year studentship covers tuition fees and provides a tax free stipend at £18,000 per annum.

How to apply
To apply, please send a copy of your CV and a cover letter describing why you are suitable for this PhD studentship to Nicola Tingley (). Informal enquiries can be sent to Dr. Julien Vaubourgeix ().

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