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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）是一种极其严重的人类呼吸道病原体，每年在全世界造成200多万人死亡。S.肺炎临床分离株以惊人的速度。许多临床相关的抗生素，包括戊内酰胺和万古霉素，靶向肽聚糖（PG）的生物合成。PG在细胞壁中形成决定细胞形状和大小的主要刚性结构，并作为其他肺炎球菌毒力因子共价连接的支架，包括荚膜、磷壁酸和分选酶转移蛋白。尽管其在生理学和发病机制上的重要性，但对S.肺炎和其他椭圆形卵球菌革兰氏阳性病原体。该项目的长期目标是填补这一重大知识空白的位置，相互作用，调节动力学，和功能的超分子蛋白质复合物介导的肺炎球菌PG生物合成。这个建议是基于大量的新论文和未发表的数据，证明了许多独特的和意想不到的性质PG生物合成在S。肺炎。PG生物合成是一个广泛的主题，包括PG合成和PG水解重塑。这个五年的提案包括四个协同的具体目标，解决了一些最重要的突出问题，在卵球菌PG生物合成。这四个目标在概念上与中心假设相关联，即PG合成和PG重塑酶作为动态超分子复合物起作用，其活性和相互作用彼此之间以及与细胞分裂相关联。之所以选择这些目标，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者蛋白相互作用而定位、激活并与细胞分裂阶段联系在一起。目的3将检验参与PG重构的PG水解直接与细胞分裂偶联的假设。目的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。将创新的遗传、生物化学、细胞生物学和显微镜方法的结果与定植和感染模型的结果相结合的综合策略将用于满足这种主要细菌病原体的这些目标。这一研究结果将挑战和拓展关于S.肺炎和其它卵球菌病原体。由于细胞表面对肺炎球菌的毒力至关重要，并且胞质外蛋白是可获得的和可药用的，因此期望在该提案中研究的一些关键PG合成和重塑蛋白将作为新的抗生素和疫苗候选物出现。