Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis.
Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis.
复制标题
铜绿假单胞菌代谢网络的重建以探究毒力因子合成
DOI：
10.1038/ncomms14631
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发表时间：
2017-03-07
影响因子：
16.6
通讯作者：
Papin JA
中科院分区：
文献类型：
--
作者：
Bartell JA;Blazier AS;Yen P;Thøgersen JC;Jelsbak L;Goldberg JB;Papin JA
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 of P. aeruginosa strain PA14 and update that of strain PAO1, which, together with mutant screens, enable them to identify genes uniquely critical for virulence factor production.
