Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/49150
Title: REGULATION OF CENTRAL CARBON METABOLISM IN MYCOBACTERIA
Authors: PAUL MURIMA
Keywords: Central Metabolism, Single cell, Drug Discovery
Issue Date: 26-Jun-2013
Citation: PAUL MURIMA (2013-06-26). REGULATION OF CENTRAL CARBON METABOLISM IN MYCOBACTERIA. ScholarBank@NUS Repository.
Abstract: Metabolism is a widely recognized facet of all host-pathogen interactions. Knowledge of its roles in pathogenesis, however, remains relatively incomplete. Existing studies have emphasized metabolism as a cellular function that pathogenic microbes use to fuel biomass instead of the mechanisms with which the cell regulates metabolism for optimal growth in an integrated manner with other cellular processes. For Mycobacterium species, matters aren¿t different. M. tuberculosis (Mtb) is a chronic facultative intracellular pathogen that obligately resides in humans. Within humans, Mtb chiefly utilizes ¿lipids¿ and resides within the macrophage phagosome, the cell type, and compartment most committed to its eradication. Mtb has consequently evolved its metabolic network to both maintain and propagate its survival in a hostile niche. The specific mechanism, in which its metabolic network serves these distinct, yet interdependent functions, is poorly defined. Progress in this area of systems biology (predominantly in cancer metabolism, metabolic physiology of model bacteria such as E. coli and B. subtilis) and data presented in this thesis, indicate that non-transcriptional mechanisms (e.g. metabolite¿protein interactions) are highly relevant in actually controlling metabolic flux (Chapter 3). Furthermore the results highlight a more significant role of allosteric interactions in governing metabolic flux when transcriptional control is sub-optimal (Chapter 4). These interactions are ultrasensitive, and operate at time scales lower that transcription in metabolic flux regulation. In Chapter 5 using microfluidic cultures, time-lapse microscopy and fluorescent reporters to track the single-cell dynamics of mycobacterial cell cycle and chromosomal replication, I demonstrate how environmental perturbations affect the organization of the cell cycle and DNA replication. These findings support a model where bacteria cease initiating the next round of chromosomal replication during nutrient limitation until limiting substrates, precursors accumulate or the environment changes to support rapid growth. In Chapter 6, I demonstrate how an improved understanding of bacterial central metabolism can be utilized, to design novel phenotypic screens for antibacterial drug discovery when searching for inhibitors targeting central metabolism.
URI: http://scholarbank.nus.edu.sg/handle/10635/49150
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