How does tuberculosis eat its own cell wall?

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Mycobacteria possess one of the most intricately designed and complex cell walls within the bacterial kingdom. The components that make up the cell wall all significantly contribute to the virulence of mycobacteria both agriculturally and in humans i.e. in important animals such as cows (e.g. Mycobacterium bovis) and humans (Mycobacterium tuberculosis) respectively. The base-layer of the mycobacterial cell wall is comprised of a heteropolymer called peptidoglycan. This glycan-peptide conjugate protects the cell from its turgor pressure, and provides a scaffold for the entire cell wall. Despite its importance we have an incomplete knowledge of how this wall is constructed and dissembled. In other organisms PBPs have been identified to a plethora of roles in peptidoglycan synthesis/remodelling. The M. tuberculosis genome encodes more than ten penicillin binding proteins, most of which the functions have not been explored. Key functional involvement for PBPs such as cell division and elongation have been shown to be important for organisms such as E. coli. This study will investigate and identify the function of the mycobacterial PBPs in M. tuberculosis. To understand the biosynthesis, remodeling and degradation of M. tuberculosis peptidoglycan, we will take advantage of an ordered, single-gene deletion library in M. bovis BCG as well as targeted mutational studies in strains of Mycobacterium marinum, Mycobacterium smegmatis, M. tuberculosis and E. coli. We will evaluate the fitness of strains lacking each of the non-essential PBPs under a wide variety of conditions, so that we can better understand the role of individual PBPs to the organism. This will allow us to determine if individual PBPs become more important under stress such as pH variation, redox or antimicrobial compounds which are all relevant to M. tuberculosis infection. Morphological studies will determine if the loss of any PBPs result in defects in cell division or shape. This will be paired with biochemical and structural analysis of purified PBPs to allow us to interrogate their catalytic function. This project will give us a better understanding of the mechanisms M. tuberculosis utilises for reproduction and survival in the context of environmental and infection dynamics.