The ability of intracellular pathogens to persist depends on their capacity to biochemically adapt to changes in the host's intracellular environment modulated by immune response mechanisms.  Targeted introduction of small molecules can interfere and reduce the pathogen's metabolic capacity.  We use computational systems chemical biology (SCB) methods to comparatively investigate the effects of inhibitory molecules on the tricarboxylic acid cycle (TCA) of M. tuberculosis and F. tularensis (Ft), two pathogens that infect host macrophages.  The reconstructed metabolic pathway for Ft is missing reactions present in Mtb, a slower growing pathogen.  Differences in metabolic capacity may impact several factors including intracellular localization, response to oxidative stress, and potentially response to small molecule inhibitors.  We evaluate inhibition of isocitrate lyase (ICL) during aerobic and oxidative stress conditions, and simulate the metabolic consequence of ICL disruption in both systems. We will discuss observations regarding Mtb and Ft's response given the variations in their representative metabolic models.

Comparative study of small molecule inhibition of Mycobacterium tuberculosis and Francisella tularensis

243rd National Meeting (2012)

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