Abstract
Little is known about the metabolic state of Mycobacterium tuberculosis (Mtb) inside the phagosome, a compartment inside phagocytes for killing pathogens and other foreign substances. We have developed a combined model of Mtb and human metabolism, sMtb-RECON and used this model to predict the metabolic state of Mtb during infection of the host. Amino acids are predicted to be used for energy production as well as biomass formation. Subsequently we assessed the effect of increasing dosages of drugs targeting metabolism on the metabolic state of the pathogen and predict resulting metabolic adaptations and flux rerouting through various pathways. In particular, the TCA cycle becomes more important upon drug application, as well as alanine, aspartate, glutamate, proline, arginine and porphyrin metabolism, while glycine, serine, and threonine metabolism become less important. We modeled the effect of 11 metabolically active drugs. Notably, the effect of eight could be recreated and two major profiles of the metabolic state were predicted. The profiles of the metabolic states of Mtb affected by the drugs BTZ043, cycloserine and its derivative terizidone, ethambutol, ethionamide, propionamide, and isoniazid were very similar, while TMC207 is predicted to have quite a different effect on metabolism as it inhibits ATP synthase and therefore indirectly interferes with a multitude of metabolic pathways.
Highlights
Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is an intracellular pathogen that thrives inside the phagosome of the host’s macrophages (Gengenbacher and Kaufmann, 2012; Zondervan et al, 2018)
As Mtb is known to be able to escape from the phagosome to the cytosol and no phagosomal compartment was present in RECON 2.2 we took all metabolic precursors from the cytoplasm as biomass precursors for the macrophage condition-specific biomass reaction
Model sMtb-RECON has a total of 8,987 reactions and 13.4% are from Mtb
Summary
Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is an intracellular pathogen that thrives inside the phagosome of the host’s macrophages (Gengenbacher and Kaufmann, 2012; Zondervan et al, 2018). This environment prevents obtaining accurate in vivo measurements characterizing the metabolic state of the pathogen during infection. Predictions made using GEMs are highly dependent on the objective that is being used and the constraints placed on the uptake and excretion of nutrients and metabolites. To perform predictions on in vitro growth, most often a
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