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

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. Targeting virulence rather than bacterial growth is less likely to select for antibiotic resistance, but many possible targets function in both processes. Here, the authors reconstruct a genome-scale metabolic network ofP. aeruginosastrain PA14 and update that of strain PAO1, which, together with mutant screens, enable them to identify genes uniquely critical for virulence factor production.

• Publication year

  2017

• Venue

  Nature Communications

• Publication date

  2017-03-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncomms14631PMID 28266498PMCID 5344303
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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