Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis

Jennifer Bartell, Anna S Blazier, Phillip Yen, Juliane Charlotte Thøgersen, Lars Jelsbak, Joanna B Goldberg, Jason A Papin

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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.
Original languageEnglish
Article number14631
JournalNature Communications
Volume8
Number of pages13
ISSN2041-1723
DOIs
Publication statusPublished - 2017

Cite this

Bartell, Jennifer ; Blazier, Anna S ; Yen, Phillip ; Thøgersen, Juliane Charlotte ; Jelsbak, Lars ; Goldberg, Joanna B ; Papin, Jason A. / Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis. In: Nature Communications. 2017 ; Vol. 8.
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Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis. / Bartell, Jennifer; Blazier, Anna S; Yen, Phillip; Thøgersen, Juliane Charlotte; Jelsbak, Lars; Goldberg, Joanna B; Papin, Jason A.

In: Nature Communications, Vol. 8, 14631, 2017.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Bartell, Jennifer

AU - Blazier, Anna S

AU - Yen, Phillip

AU - Thøgersen, Juliane Charlotte

AU - Jelsbak, Lars

AU - Goldberg, Joanna B

AU - Papin, Jason A

PY - 2017

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AB - 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.

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