Characterization of a putative metal transport protein in Streptococcus sanguinis

血链球菌中假定的金属转运蛋白的表征

基本信息

  • 批准号:
    9758463
  • 负责人:
  • 金额:
    $ 3.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-01-25 至 2021-01-24
  • 项目状态:
    已结题

项目摘要

Project Summary Streptococcus sanguinis is an oral bacterium that is normally considered a contributor to good oral health, but it has also been implicated as a major etiological agent of infective endocarditis (IE). IE is a serious disease caused by certain bacteria entering the bloodstream through lesions in the oral mucosa during surgery, mastication, or routine hygiene practices. Bacteria that are capable of binding to the heart valve can then proliferate, which may lead to congenital heart failure, aneurysm, or stroke. Currently, the only preventative for IE is the prescription of broad spectrum antibiotics given before dental procedures. With the increase in antibiotic resistance as well as the possibility of IE from routine hygiene activities, other preventatives are being investigated. ABC-family manganese transporters have been implicated as virulence factors for streptococcal IE and thus are putative drug targets. A secondary manganese transporter of S. sanguinis was recently identified and implicated as contributing to virulence in IE. This transporter is homologous to the ZIP family of proteins, which are traditionally associated with zinc and iron transport. This study seeks to determine the role of the secondary transporter through its regulation, as well as to investigate the amino acids responsible for manganese specificity. Aim 1 of the proposal will assess the regulation of the transporter under various oxygen, pH, and metal conditions. In Aim 2, the amino acids responsible for metal transport will be identified using site-directed mutagenesis to mutate specific residues of interest within S. sanguinis. Aim 3 will determine the metal specificity of the transporter by heterologous production and isolation of the protein, incorporation into liposomes, and assessment of its uptake specificity towards physiologically relevant transition metals by inductively coupled plasma mass spectrometry. Through these aims, the role and function of the transporter will be elucidated, enhancing our understanding of ZIP proteins and manganese-transporting proteins, especially as they relate to bacterial pathogenesis and oral competitiveness. Access and training for the appropriate instrumentation will be available for the approaches proposed in these aims in facilities within the Virginia Commonwealth University (VCU) Philips Institute for Oral Health Research, Department of Chemistry, and School of Pharmacy, as well as at Purdue University and Harvard University. Collaborators and mentors at VCU, Purdue University, and Harvard University will provide support and expertise in microbiology, bioinorganic chemistry, and molecular characterization of membrane proteins. Under the guidance of faculty members in each of these departments and institutions, this project will enhance the applicant’s knowledge of bioinorganic chemistry, protein characterization, and gene regulation as they relate to bacterial metal transport proteins and their contribution to pathogenesis and competitiveness.
项目摘要 血链球菌是一种口腔细菌,通常被认为有助于良好的口腔健康,但 它也被认为是感染性心内膜炎(IE)的主要病原体。IE是一种严重的疾病 由某些细菌在手术过程中通过口腔粘膜病变进入血液所致, 咀嚼,或常规的卫生习惯。能够与心脏瓣膜结合的细菌可以 增殖,这可能导致先天性心力衰竭、动脉瘤或中风。目前,唯一的预防措施是 IE是牙科手术前开出的广谱抗生素处方。随着...的增加 抗生素耐药性以及来自常规卫生活动的IE的可能性,其他预防措施正在进行中 调查过了。ABC家族锰转运蛋白被认为是链球菌的毒力因子 IE和因此是推定的药物靶点。血链球菌的一种次级锰转运体最近被 确定并牵涉到对IE毒力有贡献的病毒。该转运蛋白与ZIP家族同源 蛋白质,传统上与锌和铁的运输有关。这项研究试图确定 通过二级转运蛋白的调节,以及调查负责 锰的特异性。该提案的目标1将评估在各种情况下对运输商的监管 氧气、酸碱度和金属条件。在目标2中,将确定负责金属运输的氨基酸。 使用定点突变来突变血链球菌中感兴趣的特定残留物。目标3将决定 通过异源生产和分离蛋白、掺入来确定转运蛋白的金属特异性 脂质体,并评估其对生理相关过渡金属的摄取特异性 电感耦合等离子体质谱。通过这些目标,运输者的角色和功能 将被阐明,从而加深我们对ZIP蛋白和锰运输蛋白的理解, 尤其是当它们与细菌的发病机制和口腔竞争有关时。 将为这些建议的方法提供适当工具的访问和培训 旨在弗吉尼亚联邦大学(VCU)飞利浦口腔健康研究所内的设施, 化学系和药学院,以及普渡大学和哈佛大学。 VCU、普渡大学和哈佛大学的合作者和导师将提供支持和 在微生物学、生物无机化学和膜蛋白分子表征方面的专业知识。在……下面 在这些部门和机构的教职员工的指导下,这个项目将加强 申请人在生物无机化学、蛋白质特性和基因调控方面的知识 细菌金属转运蛋白及其在致病机理和竞争力中的作用。

项目成果

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