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.

项目摘要/摘要 铁是一种基本的营养物质，但在有氧环境中可能会受到限制。在另一个极端，铁 催化形成破坏细胞成分的活性氧物种，并可能有助于 抗生素致死的方式。细菌适应铁状态和维持动态平衡的能力 它们作为病原体、共生体以及在复杂生态系统中的成功。这项建议 提出了两个相关的假设：第一，铁获取系统可以快速进化以适应新的铁 存在于微生物环境中的络合物。第二，铁出口是管理中必不可少的机制 铁依赖的氧化应激与维持体内平衡。 铁载体介导的系统获取铁是一种众所周知的细菌铁清除 策略。然而，日本慢生根瘤菌和许多生物医学上的细菌物种并不相关 合成铁载体。这些细菌完全依赖于环境中的铁络合物， 包括由其他生物产生的铁载体(在这种情况下称为异铁载体)。大多数细菌 不能在实验室培养，其他人的工作识别了外源铁质载体和共生微生物 邻居是缺失的养料。我们在这里展示了日本双歧杆菌是一种很好的细菌模型 研究外含铁载体的利用。这些多组分摄取系统被认为是高度 然而，我们证明了通过单核苷酸突变来适应一种新的铁螯合物的快速进化。 虽然在发现上是新的，但很可能灵活的改编在自然界中是常见的。人类患者接受 长期使用铁载体或合成铁络合剂治疗铁负荷过高的患者 发生细菌感染，表明在这种选择压力下人类宿主内部的适应。 对细菌铁稳态的了解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有关的压力是必不可少的。此外，它是 与铁感应和运输有关，这是由一个不寻常的N-末端细胞质结构域赋予的。 最后，MBFA在功能上与铁储存联系在一起，我们想了解这一点的基础。三 提出了具体的目标。 具体目标1：表征外膜受体的可塑性以获得功能增益 允许快速适应可利用铁的突变。 具体目标2：确定和表征铁铁载体摄取的周质成分 允许快速适应可利用的铁。 具体目标3：阐明铁输出子MBFA的机制并表征其功能 与铁储存蛋白细菌铁蛋白的关系。