title: Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease.
abstract: BACKGROUND
  Systems biology holds promise as a new approach to drug target identification and drug discovery against neglected tropical diseases. Genome-scale metabolic reconstructions, assembled from annotated genomes and a vast array of bioinformatics/biochemical resources, provide a framework for the interrogation of human pathogens and serve as a platform for generation of future experimental hypotheses. In this article, with the application of selection criteria for both Leishmania major targets (e.g. in silico gene lethality) and drugs (e.g. toxicity), a method (MetDP) to rationally focus on a subset of low-toxic Food and Drug Administration (FDA)-approved drugs is introduced.
  
  
  RESULTS
  This metabolic network-driven approach identified 15 L. major genes as high-priority targets, 8 high-priority synthetic lethal targets, and 254 FDA-approved drugs. Results were compared to previous literature findings and existing high-throughput screens. Halofantrine, an antimalarial agent that was prioritized using MetDP, showed noticeable antileishmanial activity when experimentally evaluated in vitro against L. major promastigotes. Furthermore, synthetic lethality predictions also aided in the prediction of superadditive drug combinations. For proof-of-concept, double-drug combinations were evaluated in vitro against L. major and four combinations involving the drug disulfiram that showed superadditivity are presented.
  
  
  CONCLUSIONS
  A direct metabolic network-driven method that incorporates single gene essentiality and synthetic lethality predictions is proposed that generates a set of high-priority L. major targets, which are in turn associated with a select number of FDA-approved drugs that are candidate antileishmanials. Additionally, selection of high-priority double-drug combinations might provide for an attractive and alternative avenue for drug discovery against leishmaniasis.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Chavali
authors.forename: Anna S
authors.initials: AS
authors.lastname: Blazier
authors.forename: Jose L
authors.initials: JL
authors.lastname: Tlaxca
authors.forename: Paul A
authors.initials: PA
authors.lastname: Jensen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Pearson
authors.forename: Jason A
authors.initials: JA
authors.lastname: Papin
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006801:Humans; D018320:Leishmania major / Q000235:genetics*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy*; D053858:Metabolic Networks and Pathways; D058069:Neglected Diseases / Q000188:drug therapy*; D010616:Phenanthrenes / Q000627:therapeutic use; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000962:Antimalarials; D010616:Phenanthrenes; C023768:halofantrine