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.

项目摘要/摘要铁是一种必不可少的营养素，但在有氧环境中可能会限制。在另一个极端，铁催化损害细胞成分的活性氧的形成，可以有助于抗生素杀死的方式。细菌适应铁状态并保持体内平衡的能力作为病原体，共生体和复杂生态系统的成功促进了他们的成功。这个建议解决两个相关的假设：首先，铁采集系统可以迅速发展以适应新铁微生物环境中存在的螯合物。其次，铁出口是管理的基本机制铁依赖性氧化应激和维持稳态。铁载体介导的系统获取铁是一种描述的细菌铁清除战略。然而，头hbradyrhizobium japonicum和许多生物医学相关性的细菌种类却不合成铁载体。这些细菌完全取决于环境中的铁螯合物，包括其他生物体制造的铁载体（在这种情况下称为异种载体）。大多数细菌不能在实验室中培养，而其他人则可以通过共同摄取微生物来识别异种层邻居作为缺失的营养。我们在这里表明Japonicum是一个极好的细菌模型研究异种载体的利用。这些多组分吸收系统被认为是高度的具体，我们证明了通过单核苷酸突变来适应新的铁螯合物的快速进化。尽管在发现中是新颖的，但便利适应在本质上很常见。人类患者接受长时间给药铁载体或合成铁螯合剂，以治疗铁超负荷患者发展细菌感染，表明在该选择压力下人类宿主中的适应性。了解细菌铁的稳态几乎完全集中在铁吸收上有氧环境中的生物利用度低，因此对铁出口鲜为人知。我们确定了铁出口商MBFA，并表明它对于管理与铁相关的应力至关重要。而且，是与铁感应和运输有关，这是由异常的N末端细胞质结构域赋予的。最后，MBFA在功能上与铁存储有关，我们想了解此基础。三提出了具体目标。特定目的1：表征外膜受体的可塑性以获得功能可以快速适应可用铁的突变。特定目的2：识别并表征铁铁载体吸收的周围成分允许快速适应可用的铁。特定目标3：阐明铁出口商MBFA的机制并表征其功能与铁储存蛋白细菌铁蛋白的关系。