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Mechanisms of growth and virulence in pathogenic mycobacteria

Primary Supervisor: Dr Apoorva Bhatt, School of Biosciences

Secondary supervisor: Prof. Steve Busby

PhD project title: Mechanisms of growth and virulence in pathogenic mycobacteria.

University of Registration: University of Birmingham

Project outline:

Sequenced genomes of mycobacteria, including the bovine TB pathogen Mycobacterium bovis and it’s ‘cousin’ the human pathogen Mycobacterium tuberculosis, reveal a number of genes dedicated to lipid biosynthesis and transport. These unique lipids confer a distinct quality to the mycobacterial cell wall, and play an important role in biofilm formation, adhesion, immunomodulation and virulence. Research in the lab in the past has focussed on deciphering the genetic pathways that define lipid biosynthesis and transport in pathogenic mycobacteria. We now make use of systems-based approaches to outline regulatory pathways that drive growth and cell wall biogenesis. With the use of defined mutant strains, we plan to test the molecular mechanisms underlying the following processes, and their impact on virulence using experimental models of infection:

1) Factors driving the growth of pathogenic mycobacteria.

2) Regulation of cell wall biogenesis and its effect on virulence.

3) Molecules that drive biofilm formation

References:

  1. Dokic A, Peterson E, Arrieta-Ortiz ML, Pan M, Di Maio A, Baliga N, Bhatt A. (2021) Mycobacterium abscessusbiofilms produce an extracellular matrix and have a distinct mycolic acid profile. Cell Surf 7:100051.
  2. Pickford H, Alcock E, Singh A, Kelemen G, Bhatt A. (2020) A mycobacterial DivIVA domain-containing protein involved in cell length and septation. Microbiology (Online ahead of print)
  3. Javid A, Cooper C, Singh A, Schindler S, Hänisch M, Marshall RL, Kalscheuer R, Bavro VN, Bhatt A. (2020) The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow-growing mycobacteria. Mol Microbiol 113(2):521-533.
  4. Peterson, E. J., Bailo, R., Rothchild, A. C., Arrieta‐ortiz, M. L., Kaur, A., Pan, M., Mai, D., Abidi, A. A., Cooper, C., Aderem, A., Bhatt, A*. & Baliga, N. S.* Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation. (2019) Mol Sys Biol 15, e8584.*Joint corresponding authors

BBSRC Strategic Research Priority: Sustainable Agriculture and Food:Animal Health and Welfare & Understanding the Rules of Life: Microbiology & Structural Biology & Systems Biology

Techniques that will be undertaken during the project:

  • Protein expression and purification
  • Biophysical characterisation of proteins
  • Biochemical analysis methodology including TLC, Mass Spectroscopy and NMR
  • Generation of gene knockouts and recombinant strains of pathogenic mycobacteria
  • RNA Seq of bacterial transcripts
  • Fluorescence microscopy

Contact: Dr Apoorva Bhatt, University of Birmingham