Roles of Phosphate Uptake in Pneumococcal Antibiotic Resistance and Virulence

磷酸盐吸收在肺炎球菌抗生素耐药性和毒力中的作用

• 批准号: 8416937
• 负责人: MALCOLM E. WINKLER
• 金额: $ 19.24万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416937
• 关键词: ATP-Binding Cassette Transporters; Address; Animal Model; Antibiotic Resistance; Antibiotics; Area; Attenuated; Bacteria; Bacterial Model; Bacterial Physiology; Biological Process; Cell surface; Culture Media; Data; Development; Disease; Disease Progression; Divalent Cations; Escherichia coli; Future; Genetic; Goals; Gram-Positive Bacteria; Grant; Health; Homeostasis; Human; Human Resources; Immunocompromised Host; In Vitro; Individual; Infection; Ions; Lactams; Link; Literature; Little' s Disease; Manganese; Metabolism; Metals; Methods; Modeling; Molecular Genetics; Monobactams; Mus; Mutation; Pathogenesis; Physiology; Play; Pneumococcal Colonization; Pneumococcal Infections; Population; Pump; Regulation; Regulon; Research; Resistance; Risk; Role; Route; Spectrum Analysis; Streptococcus; Streptococcus pneumoniae; Stress; System; Testing; Time; Toxic effect; Virulence; Work; Zinc; base; divalent metal; experience; in vivo; inorganic phosphate; insight; meetings; mutant; pathogen; pathogenic bacteria; resistance mechanism; respiratory; tool; uptake; vaccine development

DESCRIPTION (provided by applicant): Streptococcus pneumoniae (pneumococcus) is a major human respiratory pathogen that remains a serious health threat worldwide. Resistance of S. pneumoniae to multiple antibiotics is increasing at an alarming rate, and the population of immunocompromised individuals who are at risk for pneumococcal invasive diseases continues to grow. Relatively little is known about the roles played by pneumococcal physiology and metabolism in promoting colonization and virulence of its human host. The overall goal of this grant is to explore the roles played by inorganic phosphate (Pi) uptake and its regulation in the pathogenesis, antibiotic resistance, and metal ion homeostasis of S. pneumoniae. Pi uptake has already been implicated in pneumococcal invasive disease, but little is known about the mechanisms underlying this involvement. Several pieces of evidence show that the regulation of Pi transport in S. pneumoniae is fundamentally different from the mechanisms determined previously for model bacteria, like E. coli and B. subtilis. Therefore, this grant will challenge te current paradigms of Pi uptake that are based on these model bacterial systems and relate Pi uptake to the pathogenesis of S. pneumoniae for the first time. In addition, this work will validat and explore a new mechanism of pneumococcal ¿-lactam resistance about which nothing is known. Finally, this grant draws together several recent ideas from the scientific literature to formulate the hypothesis that cellular Pi uptake and Pi cellular amount are tied to the availabilit and toxicity of several key divalent cations, including zinc (Zn2+) and manganese (Mn2+). Four Specific Aims will be met by this grant. Aim 1 will determine whether two predicted Pi ABC transporter pumps (designated as Pst1 and Pst2) separately uptake Pi in S. pneumoniae and whether this uptake is coordinated. Another goal of Aim 1 is to develop a powerful genetic toolbox and a conceptual framework about Pi uptake and its regulation that will allow effective exploration of the topics in Aims 2-4. Aim 2 will determine the roles of the Pst1 and Pst2 Pi transporters and the likely regulators (designated as PnpRS, PhoU1, and PhoU2) in pneumococcal colonization and virulence. Aim 2 will also determine whether there are additional routes of Pi uptake during infection, besides Pst1 and Pst2. Aim 3 will determine whether increased expression of the Pst1 transporter is responsible for resistance to ¿-lactam antibiotics and whether the Pst2 transporter also plays a role. Aim 4 will explore whether there are links between Pi uptake and cellular amount and divalent metal ion homeostasis. There is a high likelihood of obtaining publishable data from this work that will serve as the basis for a future RO1 application and open up a significant new research area in S. pneumoniae. In addition, this grant has the potential to provide new targets for antibiotic and vaccine development and to provide information about an uncharacterized mechanism of ¿-lactam antibiotic resistance in this important opportunistic pathogen.

描述（由申请方提供）：肺炎链球菌（肺炎球菌）是一种主要的人类呼吸道病原体，在全球范围内仍然是一种严重的健康威胁。S的抗性。肺炎球菌对多种抗生素的耐受性正在以惊人的速度增加，并且处于肺炎球菌侵袭性疾病风险中的免疫受损个体的群体继续增长。关于肺炎球菌的生理和代谢在促进其人类宿主的定植和毒力方面所起的作用，人们知之甚少。该基金的总体目标是探索无机磷酸盐（Pi）摄取及其调节在S.肺炎。Pi的摄取已经与肺炎球菌侵袭性疾病有关，但对这种参与的机制知之甚少。有证据表明，磷在S. pneumoniae的作用机制与以前确定的模式细菌如E. coli和B.枯草杆菌。因此，这项资助将挑战目前基于这些模型细菌系统的Pi摄取范例，并将Pi摄取与S.肺炎第一次。此外，这项工作将验证和探索一种新的机制，肺炎球菌的内酰胺耐药，这是什么都不知道。最后，这项资助汇集了科学文献中的几个最新观点，以制定细胞Pi摄取和Pi细胞量与几种关键二价阳离子（包括锌（Zn 2+）和锰（Mn 2+））的可用性和毒性相关的假设。该补助金将满足四个具体目标。目的1将确定两个预测的Pi ABC转运泵（指定为Pst 1和Pst 2）是否分别摄取S中的Pi。肺炎，以及这种摄取是否协调。目标1的另一个目标是开发一个强大的遗传工具箱和一个关于Pi摄取及其调节的概念框架，这将允许有效地探索目标2-4中的主题。目的2将确定Pst 1和Pst 2 Pi转运蛋白和可能的调节剂（指定为PnpRS，PhoU 1和PhoU 2）在肺炎球菌定植和毒力中的作用。目的2还将确定在感染期间除了Pst 1和Pst 2之外是否还有其他的Pi摄取途径。目的3将确定Pst 1转运蛋白表达的增加是否是对内酰胺类抗生素耐药的原因，以及Pst 2转运蛋白是否也起作用。目的4探讨细胞磷摄取量与二价金属离子稳态之间是否存在联系。有一个很高的可能性，从这项工作中获得的可验证的数据，将作为未来的RO 1应用的基础，并开辟了一个重要的新的研究领域在S。肺炎。此外，这笔赠款有可能为抗生素和疫苗开发提供新的靶点，并提供有关这种重要的机会致病菌对内酰胺类抗生素耐药性的未表征机制的信息。