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Bacterial adaptation to iron stress

细菌对铁胁迫的适应

基本信息

批准号：
9893725
负责人：
MARK R O'BRIAN
金额：
$ 31.79万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2023-03-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Iron is an essential nutrient, but it can be limiting in aerobic environments. At the other extreme, iron catalyzes the formation of reactive oxygen species that damages cellular components, and can contribute to the mode of killing by antibiotics. The ability of bacteria to adapt to the iron status and maintain homeostasis contribute to their success as pathogens, symbionts, and in complex ecosystems generally. This proposal addresses two related hypotheses: First, iron acquisition systems can evolve rapidly to adapt to new iron chelates present in microbial environments. Second, iron export is an essential mechanism in managing iron-dependent oxidative stress and maintaining homeostasis. Iron acquisition by siderophore-mediated systems is a well-described bacterial iron scavenging strategy. However, Bradyrhizobium japonicum and many bacterial species of biomedical relevance do not synthesize siderophores. These bacteria are wholly dependent on iron chelates from the environment, including siderophores made by other organisms (termed xenosiderophores in that context). Most bacteria cannot be cultured in the lab, and work by others identify xenosiderophores from co-habiting microbial neighbors as a missing nutrient. We show here that B. japonicum is an excellent bacterial model for studying xenosiderophore utilization. These multi-component uptake systems are regarded as highly specific, yet we demonstrate rapid evolution to adapt to a new iron chelate by single nucleotide mutation. Although novel in discovery, it is likely that facile adaptation is common in nature. Human patients receiving prolonged administration of siderophores or synthetic iron chelators to treat patients with iron overload often develop bacterial infections, suggesting adaptation within the human host under that selection pressure. Understanding bacterial iron homeostasis has focused almost exclusively on iron uptake because of its low bioavailability in aerobic environments, and thus very little known about iron export. We identified the iron exporter MbfA, and show that it is essential for managing iron-related stresses. Moreover, it is implicated in iron sensing and trafficking, which is conferred by an unusual N-terminal cytoplasmic domain. Finally, MbfA is functionally linked with iron storage, and we want to understand the basis of this. Three specific aims are proposed. Specific Aim 1: Characterize the plasticity of outer membrane receptors to acquire gain-of-function mutations that allow rapid adaptation to available iron. Specific Aim 2: Identify and characterize the periplasmic components of ferric siderophore uptake that allow rapid adaptation to available iron. Specific Aim 3: Elucidate the mechanism of the iron exporter MbfA and characterize its functional relationship with the iron storage protein bacterioferritin.

项目总结/摘要铁是一种必需的营养素，但在有氧环境中可能会受到限制。在另一个极端，铁催化活性氧物质的形成，活性氧物质会损害细胞成分，抗生素的致死方式细菌适应铁状态和维持体内平衡的能力有助于它们作为病原体、共生体和在复杂生态系统中的成功。这项建议解决了两个相关的假设：第一，铁的获取系统可以迅速发展，以适应新的铁存在于微生物环境中的螯合物。第二，铁矿石出口是一个重要的机制，铁依赖性氧化应激和维持体内平衡。铁载体介导的铁获得系统是一个很好的描述细菌铁清除战略然而，日本慢生根瘤菌和许多生物医学相关的细菌物种不合成铁载体。这些细菌完全依赖于环境中的铁螯合物，包括由其他生物体产生的铁载体（在该上下文中称为异铁载体）。大多数细菌不能在实验室中培养，其他人的工作是从共存的微生物中鉴定出异铁载体。邻居是一种缺失的营养素。我们在这里表明，B。japonicum是一个很好的细菌模型，研究异种铁载体的利用。这些多组分吸收系统被认为是高度具体来说，我们证明了通过单核苷酸突变快速进化以适应新的铁螯合物。虽然在发现上是新颖的，但很可能在自然界中容易适应是常见的。人类患者接受长期施用铁载体或合成铁螯合剂以治疗铁过载患者通常发展为细菌感染，这表明人类宿主在这种选择压力下进行了适应。了解细菌铁稳态几乎完全集中在铁的吸收，因为它有氧环境中的生物利用度低，因此对铁输出知之甚少。我们确定了铁出口商MbfA，并表明这是至关重要的管理铁相关的压力。而且是涉及铁传感和运输，这是由一个不寻常的N-末端胞质结构域赋予。最后，MbfA在功能上与铁储存有关，我们想了解这一点的基础。三提出了具体目标。具体目标1：表征外膜受体获得功能获得的可塑性这些突变允许快速适应可用的铁。具体目标2：鉴定和表征铁载体摄取的周质组分，快速适应铁元素。具体目标3：阐明铁输出蛋白MbfA的机制并表征其功能与铁储存蛋白细菌铁蛋白的关系。