Metabolic Modeling of Tuberculosis Persisters

Mycobacterium tuberculosis continues to be a global health problem, aided by the the ability of the organism to persist in human hosts. A milieu of changes occur during the transition from uninterrupted growth to stress-induced persistence, such as: reduction of intracellular ATP and NAD concentrations, decrease of RNA and protein turnover, changes to cell wall morphology, and the induction of triacylglyceride production. Metabolic modeling via flux balance analysis can be used to test the role of individual changes in enhancing fitness of Mycobacterium tuberculosis. We implement a revised objective function to reflect a cessation of replicative activity, and evaluate changes in fitness relative to maintaining the conventional replicative phenotype. We also assess a static optimization dynamic FBA model to evaluate the effect of these changes in a time-longitudinal fashion, with the goal of determining if experimentally reported changes have a direct role in prolonging the lifetime of Mycobacterium tuberculosis under stress conditions. We also aim to identify pathway level changes that occur during persistence, and seek to identify reaction targets critical to survival of the persistence model.