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Creating a systematic mycobacterial stress-response map

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

Bacterial chemical-genomics screens can quantify the impact of each gene on the fitness of the organism subjected to a large number of chemical/environmental perturbations. Chemical-genomics enables the discovery of gene function and facilitates the mapping of pathways, often leading to the identification of drug primary/secondary targets.

Despite Mycobacterium tuberculosis being a major threat to global health, systematic studies using chemical-genomic approaches have not been conducted. M. tuberculosis is difficult to genetically manipulate and requires containment level 3 facilities. For those reasons, the tuberculosis (TB) research community established the bovine TB pathogen Mycobacterium bovis BCG as a model strain. It shares high sequence similarity (99%) to M. tuberculosis, is used as a TB vaccine strain, and biological findings are transferrable to M. tuberculosis. This project will use an ordered single deletion library of M. bovis BCG to understand its genome-wide stress-response in order to dissect envelope biogenesis in M. tuberculosis. This has huge implication to our understanding of mycobacterial cell biology and might identify novel drug targets. The Ph.D. candidate can choose one, or both of the following research objectives (RO).

RO_1: Chemical-genomics to profile genome-wide stress-response of M. bovis BCG

Using state-of-the-art high-throughput screening facilities the goal is to develop a robust method that allows to screen M. bovis BCG against perturbations (antimicrobials, environmental stresses etc.) in order to identify key enzymes for mycobacterial envelope biosynthesis. To illustrate the nature of such a project, I advise to read publication 1.

Training: microbial systems biology - design, application data-analysis of high-throughput screen;

RO_2: Characterisation of key players involved in mycobacterial envelope biogenesis

Using appropriate molecular biology tools, the goal is to decipher the molecular mechanism of pathways and complexes important for mycobacterial envelope biogenesis. Investigated hits can be derived of RO_1, or based on excising preliminary data the Banzhaf laboratory possess. The Ph.D candidate can get trained on a broad range of molecular biological techniques available at the Banzhaf laboratory and its collaborators. To illustrate the nature of such a project, I advise to read publication 2.

Training: microbial cell biology, biochemistry, structural biology (Dr. Andrew Lovering, UoB), advanced biochemistry (Patrick Moynihan).

References

1. Kritikos, G., Banzhaf, M., Herrera-Dominguez, L., Koumoutsi, A., Wartel, M., Zietek, M., and Typas, A. (2017). A tool named Iris for versatile high-throughput phenotyping in microorganisms. Nature microbiology

2. Typas, A., Banzhaf, M., van den Berg van Saparoea, B., Verheul, J., Biboy, J., Nichols, R.J., Zietek, M., Beilharz, K., Kannenberg, K., von Rechenberg, M., et al. (2010). Regulation of peptidoglycan synthesis by outer-membrane proteins. Cell

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