Molecular and biochemical characterisation of mycobacterial cell wall drug targets - Lipoarabinomannan

Grover, Shipra (2014). Molecular and biochemical characterisation of mycobacterial cell wall drug targets - Lipoarabinomannan. University of Birmingham. Ph.D.

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Abstract

A recent surge in emergence of drug resistant strains of Mycobacterium tuberculosis, the etiological agent of tuberculosis has highlighted the importance of developing new therapeutics and devising novel strategies for effective management of this disease. The cell wall of M. tuberculosis is a major determinant of high level drug resistance demonstrated by this pathogen. Therefore pathways for the synthesis of its components and their regulation have remained an attractive drug target. In this study, the pathway for decaprenyl phosphate recycling emerges as a new target and illustrates a possible mechanism of resistance to the recently discovered anti-tubercular compounds, Benzothiazinones. Additionally, the newly identified Lac-I type transcriptional regulator IpsA, sheds light on an intricate regulatory network for synthesis of cell wall components, such as phosphatidyl inositol based lipoglycans. Since the pathway is critical for growth in members of Corynebacterineae, it provides for an untapped resource for designing novel inhibitors against the pathogenic species M. tuberculosis and Corynebacterium diphtheriae. This work also explores new approaches for design of anti-tubercular compounds against cell wall glycosyltransferases, such as ‘co-targeting’ of interacting transferases as revealed by protein-protein interaction studies and utilising the concept of ‘polar hydrophobicity’ in the design of ‘suicide inhibitors’ of transferase activity.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):