PhD Research Project: Dissecting cell wall metabolism in pathogenic mycobacteria

Tuberculosis is the single most deadly infectious disease in the world. The rise in multi- and extensively-drug resistant strains of Mycobacterium tuberculosis, the causative agent of TB, has highlighted the urgent need for new antibiotics. Our group attempts to address this by answering the general question “What are the unique features of mycobacteria that we can exploit as therapeutic targets?” One such feature is the unique mycobacterial cell wall that is essential for the survival of these bacteria.

The bedrock of the mycobacterial cell wall is a component called peptidoglycan. Dozens of different genes are involved in the metabolism of this cell wall component. Despite the availability of the sequenced genome for many years, however, we still do not know the function or purpose of many of these proteins. Current projects in the lab are looking at both the biosynthesis and degradation of peptidoglycan in mycobacteria. To do this we combine molecular genetics, biochemistry, structural biology and fluorescence microscopy. We complement this work by using targeted phenotypic screens to identify genes important to particular pathways in cell wall biosynthesis.

Key Experimental skills involved:

In this project students will learn or enhance existing skills in molecular biology and biochemistry. Molecular studies will involve the cloning, expression and purification of proteins, site directed mutagenesis and assay development. Bacterial genetics will be exploited to determine the role of individual genes within M. tuberculosis and closely related species. Novel fluorescent probes and phenotypic markers will be used for both biochemistry and the evaluation of mutant strains of mycobacteria.

Funding Notes

All applicants should indicate in their applications how they intend to fund their studies. We have a thriving community of international PhD students and encourage applications at any time from students able to find their own funding or who wish to apply for their own funding (e.g. Commonwealth Scholarship, Islamic Development Bank).

The postgraduate funding database provides further information on funding opportunities available http://www.birmingham.ac.uk/postgraduate/funding/FundingFilter.aspx and further information is also available on the School of Biosciences website http://www.birmingham.ac.uk/schools/biosciences/courses/postgraduate/phd.aspx

References

Abrahams, K. A., et al. (2016) Identification of KasA as the cellular target of an anti-tubercular scaffold. Nat Commun. 7, 12581

Maranha, A., Moynihan, P. J., et al. (2015) Octanoylation of early intermediates of mycobacterial methylglucose lipopolysaccharides. Sci. Rep. 5, 13610

Moynihan, P. J., and Clarke, A. J. (2014) Mechanism of action of peptidoglycan O-acetyltransferase B involves a Ser-His-Asp catalytic triad. Biochemistry. 53, 6243–6251

Baker, P., Ricer, T., Moynihan, P. J., et al. (2014) P. aeruginosa SGNH hydrolase-like proteins AlgJ and AlgX have similar topology but separate and distinct roles in alginate acetylation. PLoS Pathog. 10, e1004334

Moynihan, P. J., and Clarke, A. J. (2014) Substrate Specificity and Kinetic Characterization of Peptidoglycan O-Acetyltransferase B from Neisseria gonorrhoeae. J Biol Chem. 289, 16748–16760