Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets

Semin Immunol. 2014 Dec;26(6):610-22. doi: 10.1016/j.smim.2014.09.013. Epub 2014 Oct 23.


Systems-level metabolic network reconstructions and the derived constraint-based (CB) mathematical models are efficient tools to explore bacterial metabolism. Approximately one-fourth of the Mycobacterium tuberculosis (Mtb) genome contains genes that encode proteins directly involved in its metabolism. These represent potential drug targets that can be systematically probed with CB models through the prediction of genes essential (or the combination thereof) for the pathogen to grow. However, gene essentiality depends on the growth conditions and, so far, no in vitro model precisely mimics the host at the different stages of mycobacterial infection, limiting model predictions. These limitations can be circumvented by combining expression data from in vivo samples with a validated CB model, creating an accurate description of pathogen metabolism in the host. To this end, we present here a thoroughly curated and extended genome-scale CB metabolic model of Mtb quantitatively validated using 13C measurements. We describe some of the efforts made in integrating CB models and high-throughput data to generate condition specific models, and we will discuss challenges ahead. This knowledge and the framework herein presented will enable to identify potential new drug targets, and will foster the development of optimal therapeutic strategies.

Keywords: Constraint-based metabolic model; Gene essentiality; Metabolic model; Metabolic state; Mycobacterium tuberculosis; Systems biology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Carbon Isotopes
  • Drug Resistance, Multiple, Bacterial / genetics
  • Gene Expression Regulation, Bacterial*
  • Gene Regulatory Networks
  • Genome, Bacterial*
  • Host-Pathogen Interactions
  • Humans
  • Metabolic Networks and Pathways / genetics*
  • Models, Statistical*
  • Molecular Targeted Therapy
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism*
  • Systems Biology
  • Tuberculosis, Multidrug-Resistant / drug therapy
  • Tuberculosis, Multidrug-Resistant / metabolism
  • Tuberculosis, Multidrug-Resistant / microbiology
  • Tuberculosis, Multidrug-Resistant / pathology
  • Tuberculosis, Pulmonary / drug therapy
  • Tuberculosis, Pulmonary / metabolism
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / pathology


  • Antitubercular Agents
  • Bacterial Proteins
  • Carbon Isotopes