Heme Scavenging and Uptake by Haemophilus ducreyi

杜克雷嗜血杆菌的血红素清除和摄取

• 批准号: 8133944
• 负责人: EDWARD John COLLINS
• 金额: $ 18.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133944
• 关键词: Antibiotics; Award; Bacteria; Bacteriology; Binding; Binding Sites; Calorimetry; Carrier Proteins; Categories; Cell Surface Receptors; Centers for Disease Control and Prevention (U.S.); Collaborations; Development; Disease; Extreme drug resistant tuberculosis; Family; Genital system; Genus Mycobacterium; Goals; Growth; Heme; Heme Iron; Hemoglobin; Hemophilus ducreyi; Human; Iron; Laboratories; Lead; Link; Measures; Membrane; Membrane Proteins; Modeling; Mutation; Nature; Nutrient; Organism; Proteins; Proton-Motive Force; Role; Sequence Alignment; Sexually Transmitted Agents; Site; Site-Directed Mutagenesis; Source; Staphylococcus aureus; Structure; Surface Plasmon Resonance; Techniques; Theft; Titrations; Transferrin; Ulcer; Virulence; heme receptor; innovation; mutant; pathogen; pathogenic bacteria; periplasm; public health relevance; receptor; research study; resistant strain; structural biology; uptake

DESCRIPTION (provided by applicant): Although iron is abundant in nature, the concentration of free iron is approximately 10-18 M in the human host, where the majority of iron is sequestered in host proteins such as transferrin and hemoglobin (Hb). To overcome iron scarcity, human bacterial pathogens have evolved numerous mechanisms to acquire iron. One such mechanism is the expression of cell surface receptors specific for host heme-containing proteins. Haemophilus ducreyi, the causative agent of the sexually transmitted genital ulcer disease chancroid, expresses only one iron-scavenging mechanism required for virulence. This iron-scavenging protein is a Hb receptor termed HgbA. HgbA belongs to a large family of outer membrane proteins that are dependent on TonB that link energy via the proton-motive force of the inner membrane to transport in the outer membrane. Although TonB-dependent receptors are structurally similar, the mechanisms to acquire iron or heme from different substrates appear to be different. Furthermore, no structures of Hb-binding/transport proteins have been determined so far, even though most pathogens express proteins to extract heme from Hb. Very little is known specifically about heme uptake from Hb in H. ducreyi. Determining the mechanism of iron/heme acquisition of H. ducreyi may lead to the development of new antibiotic strategies targeting iron acquisition, which may impact all pathogens, including those defined by the CDC as category A select agents. Our short-term goal is to determine how HgbA is able to bind its substrate Hb, how it removes heme from Hb, and how HgbA transports heme to the periplasm. Our long-term goal is to understand heme uptake from Hb using H. ducreyi as a model of heme scavenging from Hb in pathogenic bacteria. Using a combination of bacteriology and biophysical techniques, we will explore the structure and function of the HgbA heme receptor from H. ducreyi. PUBLIC HEALTH RELEVANCE: Iron is extremely scarce and so bacterial pathogens have developed mechanisms to steal iron from the human host. This proposal describes experiments to explore how a bacterium called H. ducreyi, is able to bind and remove the iron containing molecule heme from hemoglobin.

描述（由申请人提供）：虽然铁在自然界中含量丰富，但在人类宿主中游离铁的浓度约为10-18 M，其中大部分铁被隔离在宿主蛋白质中，例如转铁蛋白和血红蛋白（Hb）。为了克服铁缺乏，人类细菌病原体已经进化出多种获取铁的机制。其中一种机制是表达宿主含血红素蛋白特异的细胞表面受体。杜克雷嗜血杆菌是性传播生殖器溃疡病软下疳的病原体，仅表达一种毒力所需的铁清除机制。这种铁清除蛋白是一种 Hb 受体，称为 HgbA。 HgbA 属于一大类外膜蛋白，依赖于 TonB，通过内膜的质子动力将能量连接到外膜中进行运输。尽管 TonB 依赖性受体在结构上相似，但从不同底物获取铁或血红素的机制似乎不同。此外，尽管大多数病原体表达从 Hb 中提取血红素的蛋白质，但迄今为止尚未确定 Hb 结合/转运蛋白的结构。关于杜克雷氏菌从 Hb 中摄取血红素的具体情况知之甚少。确定杜克雷螺杆菌获取铁/血红素的机制可能会导致针对铁获取的新抗生素策略的开发，这可能会影响所有病原体，包括 CDC 定义为 A 类选择制剂的病原体。我们的短期目标是确定 HgbA 如何能够结合其底物 Hb、如何从 Hb 中去除血红素以及 HgbA 如何将血红素转运至周质。我们的长期目标是使用 H. ducreyi 作为病原菌中 Hb 清除血红素的模型来了解 Hb 中血红素的摄取。我们将结合细菌学和生物物理技术，探索杜克雷菌 HgbA 血红素受体的结构和功能。 公共健康相关性：铁极其稀缺，因此细菌病原体已经形成了从人类宿主中窃取铁的机制。该提案描述了探索杜克雷杆菌（H. ducreyi）的细菌如何能够结合并去除血红蛋白中的含铁分子血红素的实验。