Genome-scale metabolic modeling reveals increased reliance on valine catabolism in clinical isolates of Klebsiella pneumoniae.
Genome-scale metabolic modeling reveals increased reliance on valine catabolism in clinical isolates of Klebsiella pneumoniae.
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DOI：
10.1038/s41540-022-00252-7
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发表时间：
2022-10-28
影响因子：
4
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中科院分区：
文献类型：
--
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碳青霉烯类耐药肠杆菌科细菌引起的感染最近已成为美国和欧洲住院患者面临的最紧迫威胁之一。到目前为止，这些感染最常见的病原体是肺炎克雷伯氏菌，经常表现为医院获得性肺炎，即使使用抗菌药物干预，死亡率也约为50%。我们对先前从实验室和临床分离株的体外表征中收集的数据进行了转录组学分析，这些数据揭示了分离株类型中多种主代谢调节因子表达的变化。代谢以前已被证明是抗菌治疗的有效靶点，基因组规模的代谢网络重建（GENRE）提供了一种强有力的手段来加速计算机识别潜在靶点。将这些技术与转录组荟萃分析相结合，我们利用K. pneumoniae（iYL 1228）来鉴定新的治疗靶点。功能代谢分析表明，临床分离相关的上下文特定的模型的组成和代谢活性显着不同于实验室分离相关的细菌模型。此外，我们确定了增加的L-缬氨酸在临床分离物特异性生长模拟的催化剂。这些发现保证了将来研究缬氨酸转氨酶抑制剂作为抗K.肺炎感染。
Infections due to carbapenem-resistant Enterobacteriaceae have recently emerged as one of the most urgent threats to hospitalized patients within the United States and Europe. By far the most common etiological agent of these infections is Klebsiella pneumoniae, frequently manifesting in hospital-acquired pneumonia with a mortality rate of ~50% even with antimicrobial intervention. We performed transcriptomic analysis of data collected previously from in vitro characterization of both laboratory and clinical isolates which revealed shifts in expression of multiple master metabolic regulators across isolate types. Metabolism has been previously shown to be an effective target for antibacterial therapy, and genome-scale metabolic network reconstructions (GENREs) have provided a powerful means to accelerate identification of potential targets in silico. Combining these techniques with the transcriptome meta-analysis, we generated context-specific models of metabolism utilizing a well-curated GENRE of K. pneumoniae (iYL1228) to identify novel therapeutic targets. Functional metabolic analyses revealed that both composition and metabolic activity of clinical isolate-associated context-specific models significantly differs from laboratory isolate-associated models of the bacterium. Additionally, we identified increased catabolism of L-valine in clinical isolate-specific growth simulations. These findings warrant future studies for potential efficacy of valine transaminase inhibition as a target against K. pneumoniae infection.
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影响因子：
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作者：
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