Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus.
Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus.
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DOI：
10.1371/journal.ppat.1011531
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发表时间：
2023-07
期刊：
影响因子：
6.7
通讯作者：
Parker, Dane
中科院分区：
文献类型：
--
作者：
Kim, Jisun;Kim, Gyu-Lee;Norambuena, Javiera;Boyd, Jeffrey M.;Parker, Dane
金黄色葡萄球菌是一种重要的病原体，通过多种感染途径导致重大疾病。我们最近发表了一个转座子测序（Tn-seq）屏幕在小鼠急性肺炎模型，并确定了一个假设的基因（SAUSA300_1902，pgl）的相似性大肠杆菌的内酯酶参与戊糖磷酸途径（PPP），这是条件必需的。关于PPP在S.金黄色。我们在这里表明，pgl的突变显着影响ATP水平和呼吸。pgl突变体和亲本菌株的RNA-seq分析鉴定了葡萄糖和葡糖酸盐的基因表达的补偿性变化以及嘧啶生物合成位点的减少。这些差异也通过无偏代谢组学研究和13 C标记实验而明显，这些实验显示pgl的突变导致嘧啶代谢的减少，包括核糖-5P，UMP和GMP的减少。这些核苷酸减少影响生物膜中细胞外DNA的量并减少生物膜形成。突变还限制了菌株抵抗过氧化氢和百草枯诱导的氧化损伤的能力，以及随后在巨噬细胞内的细胞内存活。壁磷壁酸的变化影响对过氧化氢的敏感性。我们在三种不同的感染模型中证明了这些变化对毒力的重要性，包括呼吸道，皮肤和败血症，证明了在所有模型中需要适当的PPP功能。这项工作表明了代谢在S.金黄色葡萄球菌致病性。金黄色葡萄球菌是引起多种疾病的重要原因。由于其对抗生素的耐药性和缺乏疫苗，了解其基本生理学的研究对于确定潜在的新治疗途径非常重要。在这项研究中，我们研究了S的一个方面的作用。金黄色葡萄球菌代谢：戊糖磷酸途径。我们证明，通过这一途径的碳通量减少不仅会导致细菌产生能量的能力中断，还会影响其引起感染的能力的多个方面。我们证实了这些变化在多种感染模型中的影响，以反映不同的疾病S。引起的疾病这项工作表明，新陈代谢不仅影响细菌的能量需求，而且可以影响在生物体引起疾病的能力中发挥直接作用的重要功能。
Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing (Tn-seq) screen in a mouse acute pneumonia model and identified a hypothetical gene (SAUSA300_1902, pgl) with similarity to a lactonase of Escherichia coli involved in the pentose phosphate pathway (PPP) that was conditionally essential. Limited studies have investigated the role of the PPP in physiology and pathogenesis of S. aureus. We show here that mutation of pgl significantly impacts ATP levels and respiration. RNA-seq analysis of the pgl mutant and parent strains identified compensatory changes in gene expression for glucose and gluconate as well as reductions in the pyrimidine biosynthesis locus. These differences were also evident through unbiased metabolomics studies and 13C labeling experiments that showed mutation of pgl led to reductions in pyrimidine metabolism including decreases in ribose-5P, UMP and GMP. These nucleotide reductions impacted the amount of extracellular DNA in biofilms and reduced biofilm formation. Mutation also limited the capacity of the strain to resist oxidant damage induced by hydrogen peroxide and paraquat and subsequent intracellular survival inside macrophages. Changes in wall teichoic acid impacted susceptibility to hydrogen peroxide. We demonstrated the importance of these changes on virulence in three different models of infection, covering respiratory, skin and septicemia, demonstrating the need for proper PPP function in all models. This work demonstrates the multifaceted role metabolism can play in multiple aspects of S. aureus pathogenesis. Staphylococcus aureus is an important cause of a variety of diseases. Due to its propensity to be resistant to antibiotics and the absence of a vaccine, studies to understand its fundamental physiology are important identify potential new avenues for treatment. In this study we investigated the role of one aspect of S. aureus metabolism: the pentose phosphate pathway. We demonstrated that decreased carbon flux through this pathway not only led to disruptions in the ability of the bacteria to generate energy but also influence multiple facets of its ability to cause infection. We confirmed the impact of these changes in multiple models of infection to reflect the varied diseases S. aureus can cause. This work demonstrated that metabolism does not merely impact the energy requirements of bacteria but can impact important functions that play direct roles in the organism’s ability to cause disease.
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影响因子：
7.4
作者：
Melamud E;Vastag L;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
3.7
作者：
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影响因子：
3.2
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6.4
作者：
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通讯作者：
Bayles KW
影响因子：
6.7
作者：
Grosser MR;Paluscio E;Thurlow LR;Dillon MM;Cooper VS;Kawula TH;Richardson AR
通讯作者：
Richardson AR