title: Targeting pathogen metabolism without collateral damage to the host.
abstract: The development of drugs that can inactivate disease-causing cells (e.g. cancer cells or parasites) without causing collateral damage to healthy or to host cells is complicated by the fact that many proteins are very similar between organisms. Nevertheless, due to subtle, quantitative differences between the biochemical reaction networks of target cell and host, a drug can limit the flux of the same essential process in one organism more than in another. We identified precise criteria for this 'network-based' drug selectivity, which can serve as an alternative or additive to structural differences. We combined computational and experimental approaches to compare energy metabolism in the causative agent of sleeping sickness, Trypanosoma brucei, with that of human erythrocytes, and identified glucose transport and glyceraldehyde-3-phosphate dehydrogenase as the most selective antiparasitic targets. Computational predictions were validated experimentally in a novel parasite-erythrocytes co-culture system. Glucose-transport inhibitors killed trypanosomes without killing erythrocytes, neurons or liver cells.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics and Systems Biology Centre for Energy Metabolism and Ageing, Center for Liver, Digestive and Metabolic Diseases, Groningen, The Netherlands.|Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands.
authors.forename: Jurgen R
authors.initials: JR
authors.lastname: Haanstra
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics and Systems Biology Centre for Energy Metabolism and Ageing, Center for Liver, Digestive and Metabolic Diseases, Groningen, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Gerding
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, The Netherlands.
authors.forename: Amalia M
authors.initials: AM
authors.lastname: Dolga
authors.affiliation: University of Groningen, University Medical Center Groningen, European Research Institute for the Biology of Ageing, Groningen, The Netherlands.
authors.forename: Freek J. H.
authors.initials: FJH
authors.lastname: Sorgdrager
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Hepatology and Gastroenterology, and Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: Manon
authors.initials: M
authors.lastname: Buist-Homan
authors.affiliation: Department of Biochemistry, Stellenbosch University, South Africa.
authors.forename: François
authors.initials: F
authors.lastname: du Toit
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Hepatology and Gastroenterology, and Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: Klaas Nico
authors.initials: KN
authors.lastname: Faber
authors.affiliation: Charité - Universitätsmedizin Berlin, Institut für Biochemie, Berlin, Germany.
authors.forename: Hermann-Georg
authors.initials: HG
authors.lastname: Holzhütter
authors.affiliation: Centre for Immunity, Infection and Evolution, Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, UK.
authors.forename: Balázs
authors.initials: B
authors.lastname: Szöör
authors.affiliation: Centre for Immunity, Infection and Evolution, Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, UK.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Matthews
authors.affiliation: Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands.|Department of Biochemistry, Stellenbosch University, South Africa.|Manchester Centre for Integrative Systems Biology, School of Chemical Engineering and Analytical Science, University of Manchester, Manchester, UK.
authors.forename: Jacky L
authors.initials: JL
authors.lastname: Snoep
authors.affiliation: Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands.|Manchester Centre for Integrative Systems Biology, School of Chemical Engineering and Analytical Science, University of Manchester, Manchester, UK.|Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hans V
authors.initials: HV
authors.lastname: Westerhoff
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics and Systems Biology Centre for Energy Metabolism and Ageing, Center for Liver, Digestive and Metabolic Diseases, Groningen, The Netherlands.|Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bakker
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors; D006019:Glycolysis / Q000187:drug effects; D006790:Host-Parasite Interactions / Q000187:drug effects*; D006801:Humans; D009474:Neurons / Q000187:drug effects; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000472:pathogenicity; D014353:Trypanosomiasis, African / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000977:Antiparasitic Agents; D051246:Glucose Transport Proteins, Facilitative; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005947:Glucose