title: Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling.
abstract: BACKGROUND
  In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data.
  
  
  RESULTS
  We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs.
  
  
  CONCLUSIONS
  Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas.
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Germany. ; Centre de Recherche en Santé de Nouna, Nouna, Burkina Faso.
authors.forename: J
authors.initials: J
authors.lastname: Zirkel
authors.forename: A
authors.initials: A
authors.lastname: Cecil
authors.forename: F
authors.initials: F
authors.lastname: Schäfer
authors.forename: S
authors.initials: S
authors.lastname: Rahlfs
authors.forename: A
authors.initials: A
authors.lastname: Ouedraogo
authors.forename: K
authors.initials: K
authors.lastname: Xiao
authors.forename: S
authors.initials: S
authors.lastname: Sawadogo
authors.forename: B
authors.initials: B
authors.lastname: Coulibaly
authors.forename: K
authors.initials: K
authors.lastname: Becker
authors.forename: T
authors.initials: T
authors.lastname: Dandekar