Department of Chemical Engineering, Queen's University, Kingston, Canada.
Department of Computer Science, University of Tübingen, 72076, Tübingen, Germany.
Commun Biol. 2023 Feb 10;6(1):165. doi: 10.1038/s42003-023-04540-8.
Pseudomonas aeruginosa is one of the leading causes of hospital-acquired infections. To decipher the metabolic mechanisms associated with virulence and antibiotic resistance, we have developed an updated genome-scale model (GEM) of P. aeruginosa. The model (iSD1509) is an extensively curated, three-compartment, and mass-and-charge balanced BiGG model containing 1509 genes, the largest gene content for any P. aeruginosa GEM to date. It is the most accurate with prediction accuracies as high as 92.4% (gene essentiality) and 93.5% (substrate utilization). In iSD1509, we newly added a recently discovered pathway for ubiquinone-9 biosynthesis which is required for anaerobic growth. We used a modified iSD1509 to demonstrate the role of virulence factor (phenazines) in the pathogen survival within biofilm/oxygen-limited condition. Further, the model can mechanistically explain the overproduction of a drug susceptibility biomarker in the P. aeruginosa mutants. Finally, we use iSD1509 to demonstrate the drug potentiation by metabolite supplementation, and elucidate the mechanisms behind the phenotype, which agree with experimental results.
铜绿假单胞菌是医院获得性感染的主要原因之一。为了解析与毒力和抗生素耐药性相关的代谢机制，我们开发了一个更新的铜绿假单胞菌基因组尺度模型 (GEM)。该模型 (iSD1509) 是一个经过广泛校对的三隔间、质量和电荷平衡的 BiGG 模型，包含 1509 个基因，是迄今为止任何铜绿假单胞菌 GEM 中基因含量最大的。它具有最高的预测准确性，高达 92.4%（基因必需性）和 93.5%（底物利用）。在 iSD1509 中，我们新添加了一个最近发现的泛醌-9生物合成途径，该途径是厌氧生长所必需的。我们使用修改后的 iSD1509 来证明毒力因子（吩嗪）在生物膜/缺氧条件下病原体生存中的作用。此外，该模型可以从机制上解释铜绿假单胞菌突变体中药物敏感性生物标志物的过度产生。最后，我们使用 iSD1509 来证明代谢物补充的药物增效作用，并阐明表型背后的机制，这些机制与实验结果一致。
