title: Systematic Identification of Anti-Fungal Drug Targets by a Metabolic Network Approach.
abstract: New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness ("hubs"), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaltdorf
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg Würzburg, Germany.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Srivastava
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg Würzburg, Germany.
authors.forename: Shishir K
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg Würzburg, Germany.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Liang
authors.affiliation: Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Friedrich-Alexander University Erlangen-Nürnberg, University Hospital of Erlangen Erlangen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Binder
authors.affiliation: Division of Molecular Biology/Biocenter, Medical University Innsbruck Innsbruck, Austria.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Dietl
authors.affiliation: Aspergillus and Antifungal Research Laboratory, Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University Tel-Aviv, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Meir
authors.affiliation: Division of Molecular Biology/Biocenter, Medical University Innsbruck Innsbruck, Austria.
authors.forename: Hubertus
authors.initials: H
authors.lastname: Haas
authors.affiliation: Aspergillus and Antifungal Research Laboratory, Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University Tel-Aviv, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Osherov
authors.affiliation: Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Friedrich-Alexander University Erlangen-Nürnberg, University Hospital of Erlangen Erlangen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Krappmann
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
keywords: antimycotics; fungicide; interaction; metabolism; modeling; structure; targets