The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2970 Hørsholm, Denmark.
Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
Nat Commun. 2017 Mar 7;8:14631. doi: 10.1038/ncomms14631.
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.
机会性病原体中的毒力相关途径是假定的治疗靶点，与生长必需途径中的靶点相比，它们的耐药潜力可能较低。然而，毒力相关靶点的疗效可能受到与代谢相关的毒力相关基因的贡献的影响。我们使用铜绿假单胞菌 PA14 菌株的基因组规模代谢网络重建和更新、扩展的 P. aeruginosa 菌株 PAO1 重建来评估生长和毒力相关途径之间的复杂相互关系。PA14 重建考虑了 112 个毒力相关基因和毒力因子合成途径的活性，这些途径产生了 17 种独特的化合物。我们整合了八项已发表的基因组规模突变体筛选，以验证丰富培养基中基因必需性预测，使屏幕内差异背景化，并评估毒力相关基因在必需性数据集上的分布。计算筛选进一步阐明了抑制毒力因子合成与生长之间的相互连接。使用 PA14 转座子突变体成功验证了选定基因扰动，证明了基于模型的治疗靶点筛选的实用性。
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