Metabolic Profiling of a Human Pathogen: First Flux Map of Mycobacterium tuberculosis

Little is known about the metabolism of Mycobacterium tuberculosis (Mtb) and how it can survive in the human body

despite antibiotic treatment. Mtb is the major bacterial cause of tuberculosis (TB) with approx. 2 million deaths worldwide per year while it infects approximately one-third of the human population. In close collaboration with the group of Johnjoe McFadden at the University of Surrey, GB, the Modeling and Simulation group at IBG-1: Biotechnology succeeded in deriving metabolic flux maps of the human pathogen. These maps make the activity of central carbon transport routes of Mtb visible for the first time. The results are published in PLoS

Pathogens (PLoS Pathog. 7(7):e1002091, 2011).

The bacterium has developed an efficient survival strategy: it manipulates the immune system in a way that hinders the human “trash collectors”, the macrophages, from eliminating the pathogenic intruders. Although the macrophages should eat and destroy Mtb, the pathogen is able to persist within the macrophage cells in a latent, metabolically quiescent state for a long time. Thus TB therapy requires a strict treatment with multiple antibiotics for 9-12 months to ensure elimination of persistent bacilli and to prevent selection of resistant strains. In several parts of the world, however, such treatment is nearly impossible to sustain. Moreover, multiply drug resistant strains are increasingly common.

For biomedical research it is of fundamental importance to understand the biochemical and physiological mechanisms allowing the human pathogen to resist host defenses, in particular in persistent organisms. The carbon metabolism has been identified as a major determinant of pathogenicity of Mtb. However, little is known about Mtb’s metabolism in its in vivo hibernated state. As a first step, the pathogen was characterized ex vivo in a bioreactor at the University of Surrey.

Using data from

¹³C

tracer experiments, the first time

¹³C-metabolic flux analysis (¹³C-MFA) was utilized to quantitatively study metabolic processes. ¹³C-MFA is a

model-based method which is a specialty of

the Jülich group. The analysis

identified a novel metabolic activity motif for pyruvate dissimilation in Mtb and confirmed the pathogen’s ability of CO₂ fixation. Both findings provide objectives for future investigations in vivo and a point that could be targeted by novel drugs.