Bacterial adaptation to iron stress

细菌对铁胁迫的适应

• 批准号: 9285494
• 负责人: MARK R O'BRIAN
• 金额: $ 31.81万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285494
• 关键词: Address; Aerobic; Antibiotics; Bacteria; Bacterial Infections; Bacterial Model; Biological Availability; Bradyrhizobium; Cell physiology; Chelating Agents; Chronic; Complex; Cytoplasm; Cytoplasmic Tail; Ecosystem; Environment; Evolution; Habits; Homeostasis; Human; Iron; Iron Chelating Agents; Iron Overload; Iron-Binding Proteins; Link; Mediating; Membrane; Membrane Transport Proteins; Missense Mutation; Modeling; Mutation; N-terminal; Nature; Nucleotides; Nutrient; Organism; Oxidative Stress; Patients; Proteins; Reactive Oxygen Species; Role; Siderophores; Source; Stress; Study models; System; Testing; Transmembrane Transport; Work; gain of function mutation; genetic selection; iron (III) reductase; iron metabolism; killings; microbial; mutant; novel; pathogen; periplasm; pressure; receptor; siderophore receptors; success; trafficking; uptake

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.

项目概要/摘要 铁是一种必需营养素，但在有氧环境中可能会受到限制。在另一个极端，铁 催化活性氧的形成，破坏细胞成分，并有助于 抗生素杀死的方式。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、共生体以及在复杂生态系统中的成功。这个提议 提出了两个相关的假设：首先，铁采集系统可以快速发展以适应新的铁 存在于微生物环境中的螯合物。二、铁出口是管理的重要机制 铁依赖性氧化应激和维持体内平衡。 通过铁载体介导的系统获取铁是一种众所周知的细菌铁清除作用 战略。然而，日本慢生根瘤菌和许多具有生物医学相关性的细菌种类并不 合成铁载体。这些细菌完全依赖于环境中的铁螯合物， 包括其他生物体产生的铁载体（在这种情况下称为异铁载体）。大多数细菌 不能在实验室中培养，其他人的工作可以从共生的微生物中识别出异铁载体 邻居作为缺失的营养素。我们在此表明​​，日本芽孢杆菌是一种优秀的细菌模型 研究异铁载体的利用。这些多组分吸收系统被认为是高度 具体，但我们证明了通过单核苷酸突变可以快速进化以适应新的铁螯合物。 尽管发现很新颖，但轻松的适应在自然界中很可能很常见。人类患者接受 经常长期服用铁载体或合成铁螯合剂来治疗铁超负荷患者 产生细菌感染，这表明人类宿主在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上，因为它 在有氧环境中生物利用度低，因此对铁的输出知之甚少。我们确定了 铁出口商 MbfA，并表明它对于管理与铁相关的压力至关重要。而且，它是 参与铁感应和运输，这是由不寻常的 N 末端细胞质结构域赋予的。 最后，MbfA 在功能上与铁储存相关，我们想了解其基础。三 提出了具体目标。 具体目标 1：表征外膜受体的可塑性以获得功能 允许快速适应可用铁的突变。 具体目标 2：识别并表征铁铁载体吸收的周质成分 允许快速适应可用的铁。 具体目标 3：阐明铁输出体 MbfA 的机制并表征其功能 与储铁蛋白细菌铁蛋白的关系。