Journal article
Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark1
Infection Microbiology, Research Groups, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark2
University of Virginia3
Department of Systems Biology, Technical University of Denmark4
Infection Microbiology, Department of Systems Biology, Technical University of Denmark5
Department of Biotechnology and Biomedicine, Technical University of Denmark6
Infection Microbiology, Section for Microbial and Chemical Ecology, Department of Biotechnology and Biomedicine, Technical University of Denmark7
Atlanta8
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.
Language: | English |
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Publisher: | Nature Publishing Group |
Year: | 2017 |
Pages: | 14631 |
ISSN: | 20411723 |
Types: | Journal article |
DOI: | 10.1038/ncomms14631 |
ORCIDs: | Bartell, Jennifer , Jelsbak, Lars , 0000-0001-5226-0339 and 0000-0002-0234-7791 |