title: Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets.
abstract: 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.
authors.affiliation: Laboratory of Systems and Synthetic Biology, Wageningen University and Research Centre, Dreijenplein 10, Wageningen 6703 HB, The Netherlands.
authors.forename: Rienk A
authors.initials: RA
authors.lastname: Rienksma
authors.affiliation: Laboratory of Systems and Synthetic Biology, Wageningen University and Research Centre, Dreijenplein 10, Wageningen 6703 HB, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Suarez-Diez
authors.affiliation: Centre National de la Rescherche Scientifique (CNRS), Institut de Pharmacologie et de Biologie Structurale (UMR 5089), Department of Tuberculosis and Infection Biology and Université de Toulouse (Université Paul Sabatier, Toulouse III), IPBS, 205 Route de Narbonne, BP 64182, F-31077 Toulouse, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Spina
authors.affiliation: Laboratory of Systems and Synthetic Biology, Wageningen University and Research Centre, Dreijenplein 10, Wageningen 6703 HB, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schaap
authors.affiliation: Laboratory of Systems and Synthetic Biology, Wageningen University and Research Centre, Dreijenplein 10, Wageningen 6703 HB, The Netherlands; Lifeglimmer GmbH, Markelstrasse 38, 12163 Berlin, Germany. Electronic address: vitor.martinsdossantos@wur.nl.
authors.forename: Vitor A P
authors.initials: VA
authors.lastname: Martins dos Santos
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002247:Carbon Isotopes; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D016680:Genome, Bacterial; D054884:Host-Pathogen Interactions; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D015233:Models, Statistical; D058990:Molecular Targeted Therapy; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D049490:Systems Biology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002247:Carbon Isotopes
keywords: Constraint-based metabolic model; Gene essentiality; Metabolic model; Metabolic state; Mycobacterium tuberculosis; Systems biology