title: Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis.
abstract: Virulence-linked pathways in opportunistic pathogens are putative therapeutic targets that may be associated with less potential for resistance than targets in growth-essential pathways. However, efficacy of virulence-linked targets may be affected by the contribution of virulence-related genes to metabolism. We evaluate the complex interrelationships between growth and virulence-linked pathways using a genome-scale metabolic network reconstruction of Pseudomonas aeruginosa strain PA14 and an updated, expanded reconstruction of P. aeruginosa strain PAO1. The PA14 reconstruction accounts for the activity of 112 virulence-linked genes and virulence factor synthesis pathways that produce 17 unique compounds. We integrate eight published genome-scale mutant screens to validate gene essentiality predictions in rich media, contextualize intra-screen discrepancies and evaluate virulence-linked gene distribution across essentiality datasets. Computational screening further elucidates interconnectivity between inhibition of virulence factor synthesis and growth. Successful validation of selected gene perturbations using PA14 transposon mutants demonstrates the utility of model-driven screening of therapeutic targets.
authors.affiliation: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2970 Hørsholm, Denmark.|Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Jennifer A
authors.identifier: 0000-0003-2750-9678
authors.initials: JA
authors.lastname: Bartell
authors.affiliation: Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Anna S
authors.identifier: 0000-0001-5226-0339
authors.initials: AS
authors.lastname: Blazier
authors.affiliation: Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Phillip
authors.identifier: 0000-0002-0234-7791
authors.initials: P
authors.lastname: Yen
authors.affiliation: Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
authors.forename: Juliane C
authors.initials: JC
authors.lastname: Thøgersen
authors.affiliation: Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
authors.forename: Lars
authors.identifier: 0000-0002-5759-9769
authors.initials: L
authors.lastname: Jelsbak
authors.affiliation: Department of Pediatrics, Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis and Sleep, Children's Healthcare of Atlanta, Atlanta, Georgia 30322, USA.|Emory+Children's Center for Cystic Fibrosis Research, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia 30322, USA.
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Goldberg
authors.affiliation: Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Papin
mesh_terms: D018533:Biomass; D003470:Culture Media; D005798:Genes, Bacterial; D020043:Genes, Essential; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000096:biosynthesis; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000378:metabolism; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000096:biosynthesis*
chemical_list: D003470:Culture Media; D009842:Oligopeptides; D054852:Small Molecule Libraries; D037521:Virulence Factors; C042453:pyoverdin