Quantitative metabolomics reveals an epigenetic blueprint for iron acquisition in uropathogenic Escherichia coli.
Quantitative metabolomics reveals an epigenetic blueprint for iron acquisition in uropathogenic Escherichia coli.
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DOI：
10.1371/journal.ppat.1000305
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发表时间：
2009-02
期刊：
影响因子：
6.7
通讯作者：
Hultgren, Scott J.
中科院分区：
文献类型：
--
作者：
Henderson, Jeffrey P.;Crowley, Jan R.;Pinkner, Jerome S.;Walker, Jennifer N.;Tsukayama, Pablo;Stamm, Walter E.;Hooton, Thomas M.;Hultgren, Scott J.
细菌病原体常常因存在与铁获取相关的获得性基因而有所不同。然而，特定铁载体受体基因的存在并不能可靠地预测参与这些次生代谢物合成与运输的复杂蛋白质组装体的活性。在此，我们开发了一种基于稳定同位素稀释的新型定量代谢组学方法，以比较与肠道定植或泌尿系统疾病相关的大肠杆菌菌株所产生的铁载体的组成。由于人们认为尿路致病性大肠杆菌在感染前存在于肠道微生物组中，我们比较了复发性尿路感染个体患者的尿液和直肠分离株之间铁载体的产生情况。虽然所有菌株都产生肠杆菌素，但在尿液菌株中观察到铁载体耶尔森菌素和沙门菌素的强烈优先表达。对铁载体受体进行的常规PCR基因分型往往对这些差异不敏感。一种线性化的肠杆菌素铁载体也被鉴定为具有活性沙门菌素基因簇的菌株的产物。这些发现表明，在人类尿路病原体中，大肠杆菌次生代谢组发生了定性和定量的表观遗传优化。由于与毒力相关的生物合成途径不同于与直肠定植相关的途径，这些结果为针对毒力的治疗策略提供了思路。
尿路感染（UTIs）是全球医生治疗的最常见的细菌感染之一。尽管急性感染的症状通常通过一个疗程的抗生素得以缓解，但同一细菌菌株常常导致后续的症状性感染发作。大肠杆菌是引起尿路感染最常见的细菌，并且人们普遍认为感染菌株源自肠道，肠道中存在多种大肠杆菌菌株。在此，我们在一群复发性尿路感染患者中使用一种新型质谱技术，以确定引起尿路感染的菌株与同时存在于肠道中的其他菌株有何不同。我们发现尿液中的大肠杆菌菌株优先表达两种小分子，即耶尔森菌素和沙门菌素。这些分子被称为铁载体，意味着它们能够获取铁以支持细菌的生存和生长。这些小分子的合成和运输需要由一系列不同基因编码的蛋白质协调网络。这些发现表明，针对产生耶尔森菌素或沙门菌素的大肠杆菌菌株的新型抗生素可能是一种改进的、更具针对性的预防复发性尿路感染的策略。
Bacterial pathogens are frequently distinguished by the presence of acquired genes associated with iron acquisition. The presence of specific siderophore receptor genes, however, does not reliably predict activity of the complex protein assemblies involved in synthesis and transport of these secondary metabolites. Here, we have developed a novel quantitative metabolomic approach based on stable isotope dilution to compare the complement of siderophores produced by Escherichia coli strains associated with intestinal colonization or urinary tract disease. Because uropathogenic E. coli are believed to reside in the gut microbiome prior to infection, we compared siderophore production between urinary and rectal isolates within individual patients with recurrent UTI. While all strains produced enterobactin, strong preferential expression of the siderophores yersiniabactin and salmochelin was observed among urinary strains. Conventional PCR genotyping of siderophore receptors was often insensitive to these differences. A linearized enterobactin siderophore was also identified as a product of strains with an active salmochelin gene cluster. These findings argue that qualitative and quantitative epi-genetic optimization occurs in the E. coli secondary metabolome among human uropathogens. Because the virulence-associated biosynthetic pathways are distinct from those associated with rectal colonization, these results suggest strategies for virulence-targeted therapies. Urinary tract infections (UTIs) are among the most common bacterial infections treated by physicians worldwide. Although symptoms of acute infection are often resolved with a course of antibiotics, the same bacterial strain often causes subsequent bouts of symptomatic infection. Escherichia coli are the most common bacteria causing UTI and the infecting strains are widely believed to originate from the gastrointestinal tract where multiple E. coli strains reside. Here, we use a novel mass spectrometric technique in a population of patients with recurrent UTI to identify how strains that cause UTI differ from other strains that were present in the gastrointestinal tract at the same time. We found that urinary E. coli strains preferentially expressed two small molecules called yersiniabactin and salmochelin. These molecules are called siderophores, meaning they are able to scavenge iron to support bacterial survival and growth. Synthesis and transport of these small molecules requires a coordinated network of proteins encoded by a collection of different genes. These findings suggest that new antibiotics directed against yersiniabactin or salmochelin-producing E. coli strains may be an improved, and more targeted, strategy to prevent recurrent UTIs.
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影响因子：
3.5
作者：
CHEREPANOV, PP;WACKERNAGEL, W
通讯作者：
WACKERNAGEL, W
影响因子：
--
作者：
Murphy KC;Campellone KG
通讯作者：
Campellone KG
DOI：
10.1073/pnas.0737682100
发表时间：
2003-04-01
影响因子：
11.1
作者：
Hantke, K;Nicholson, G;Winkelmann, G
通讯作者：
Winkelmann, G
影响因子：
9.4
作者：
Johnson, JR;Kaster, N;Ling, GV
通讯作者：
Ling, GV
影响因子：
6.4
作者：
Johnson, JR;Kuskowski, MA;Vila, J
通讯作者：
Vila, J