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Supramolecular Complexes That Mediate Pneumococcal PG Biosynthesis and Virulence

介导肺炎球菌 PG 生物合成和毒力的超分子复合物

基本信息

批准号：
8507826
负责人：
MALCOLM E. WINKLER
金额：
$ 38.22万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507826
关键词：
ATP Hydrolysis ATP-Binding Cassette Transporters Accounting Address Anabolism Antibiotics Binding Biochemical Carboxypeptidase Cell Shape Cell Size Cell Wall Cell division Cell surface Cellular biology Clinical Complex Coupled Couples Data Enzymes Genetic Goals Gram-Positive Bacteria Human Hydrolysis Immune response Infection Knowledge Lactams Link Location Mediating Membrane Proteins Microscopic Modeling Multi-Drug Resistance N-Acetylmuramoyl-L-alanine Amidase Paper Passive Immunity Pathogenesis Penicillin-Binding Proteins Peptides Peptidoglycan Peripheral Physiology Play Pneumococcal Colonization Process Property Proteins Resistance development Role Scaffolding Protein Shapes Staging Streptococcus Streptococcus pneumoniae Structure Teichoic Acids Tertiary Protein Structure Testing Time Vancomycin Virulence Virulence Factors Work base capsule clinically relevant combat expectation feeding genetic regulatory protein innovation killings meetings mutant novel vaccines pathogen protein complex respiratory scaffold sortase vaccine candidate vaccine development

项目摘要

DESCRIPTION (provided by applicant): Streptococcus pneumoniae (pneumococcus) is an extremely serious human respiratory pathogen that kills well over two million people annually worldwide. Multidrug resistance is increasing in S. pneumoniae clinical isolates at an alarming rate. Many clinically relevant antibiotics, including ¿-lactams and vancomycin, target peptidoglycan (PG) biosynthesis. PG forms the major rigid structure in the cell wall that determines cell shape and size and serves as the scaffolding onto which other pneumococcal virulence factors are covalently attached, including capsule, teichoic acids, and sortase-transferred proteins. Despite its importance to physiology and pathogenesis, little is known about the supramolecular protein complexes that mediate PG biosynthesis on the cell surface of S. pneumoniae and other ellipsoid-shaped ovococcus Gram-positive pathogens. The long-term goal of this project is to fill in this major knowledge gap about the locations, interactions, regulatory dynamics, and functions of the supramolecular protein complexes that mediate pneumococcal PG biosynthesis. This proposal is based on a large body of new papers and unpublished data that demonstrates numerous unique and unexpected properties of PG biosynthesis in S. pneumoniae. PG biosynthesis is a broad topic that encompasses both PG synthesis and PG remodeling by hydrolysis. This five- year proposal consists of four synergistic Specific Aims that address some of the most important outstanding problems in ovococcus PG biosynthesis. These four Aims are conceptually linked to the central hypothesis that PG synthesis and PG remodeling enzymes function as dynamic supramolecular complexes, whose activities and interactions are choreographed with each other and with cell division. These Aims were chosen, because they will yield fundamental principles about PG biosynthesis, are supported by strong new data, are experimentally tractable, feed into each other, and will have high impact on the field. Related Aims 1 and 2 will elucidate how penicillin binding proteins (PBPs) are localized, activated, and tied to stages of cell division through interactions with a small number of essential master organizer proteins. Aim 3 will test the hypothesis that PG hydrolysis involved in PG remodeling is coupled directly to cell division. Aim 4 will determine how PG hydrolases modulate the supply of PG pentapeptide substrates used by PBPs and whether PG peptides play roles in organizing PG synthesis. A comprehensive strategy that combines results from innovative genetic, biochemical, cell biology, and microscopic approaches with those from colonization and infection models will be used to meet these Aims for this primary bacterial pathogen. Results from this proposal will challenge and expand paradigms and models about PG biosynthesis in S. pneumoniae and other ovococcus pathogens. Since the cell surface is critical to pneumococcal virulence and extracytoplasmic proteins are accessible and druggable, there is an expectation that some of the critical PG synthesis and remodeling proteins studied in this proposal will emerge as new antibiotic and vaccine candidates.

描述（由申请人提供）：肺炎链球菌（肺炎球菌）是一种极为严重的人类呼吸道病原体，每年在全世界夺去超过 200 万人的生命。肺炎链球菌临床分离株的多重耐药性正在以惊人的速度增加。许多临床相关抗生素，包括β-内酰胺和万古霉素，都以肽聚糖（PG）生物合成为目标。 PG 形成细胞壁中的主要刚性结构，决定细胞形状和大小，并作为其他肺炎球菌毒力因子共价附着的支架，包括荚膜、磷壁酸和分选酶转移蛋白。尽管其对生理学和发病机制很重要，但人们对介导肺炎链球菌和其他椭圆形卵球菌革兰氏阳性病原体细胞表面PG生物合成的超分子蛋白复合物知之甚少。该项目的长期目标是填补有关介导肺炎球菌 PG 生物合成的超分子蛋白复合物的位置、相互作用、调控动力学和功能的主要知识空白。该提案基于大量新论文和未发表的数据，这些论文和未发表的数据证明了肺炎链球菌中 PG 生物合成的许多独特和意想不到的特性。 PG 生物合成是一个广泛的主题，包括 PG 合成和通过水解进行的 PG 重塑。该五年提案由四个协同具体目标组成，旨在解决卵球菌 PG 生物合成中一些最重要的突出问题。这四个目标在概念上与中心假设相关，即 PG 合成和 PG 重塑酶作为动态超分子复合物发挥作用，其活动和相互作用相互之间以及与细胞分裂一起精心设计。选择这些目标是因为它们将产生关于 PG 生物合成的基本原理，得到强有力的新数据的支持，在实验上易于处理，相互补充，并将对该领域产生重大影响。相关目标 1 和 2 将阐明青霉素结合蛋白 (PBP) 如何通过与少量必需的主组织蛋白相互作用来定位、激活并与细胞分裂阶段相关。目标 3 将检验以下假设：参与 PG 重塑的 PG 水解与细胞分裂直接相关。目标 4 将确定 PG 水解酶如何调节 PBP 使用的 PG 五肽底物的供应以及 PG 肽是否在组织 PG 合成中发挥作用。将采用一项综合策略，将创新的遗传、生化、细胞生物学和微观方法的结果与定植和感染模型的结果相结合，以实现这种主要细菌病原体的这些目标。该提案的结果将挑战并扩展肺炎链球菌和其他卵球菌病原体中 PG 生物合成的范式和模型。由于细胞表面对肺炎球菌毒力至关重要，并且胞质外蛋白易于接近且可药物化，因此预计本提案中研究的一些关键 PG 合成和重塑蛋白将成为新的抗生素和疫苗候选物。