CopN mechanism as a key to understanding Type Three Secretion in bacteria

CopN 机制是理解细菌三型分泌的关键

• 批准号: 9305827
• 负责人: BENJAMIN W SPILLER
• 金额: $ 39.21万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305827
• 关键词: Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Binding; Binding Proteins; Binding Sites; Biochemistry; Categories; Cell membrane; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Chlamydia; Chlamydophila psittaci; Complex; Crystallization; Cytoplasm; Cytoskeleton; Cytosol; Data; Development; Drug Targeting; Drug resistance; Escherichia coli; Eukaryotic Cell; Gram-Negative Bacteria; Host Defense; Lead; Link; Mediating; Membrane; Methicillin Resistance; Microtubules; Modification; Molecular; Molecular Chaperones; Mutagenesis; Mutation; Needles; Pathogenicity; Peptides; Pharmaceutical Preparations; Process; Protein Secretion; Proteins; Pseudomonas; Public Health; Publishing; Regulation; Role; Salmonella; Shigella; Staphylococcus aureus; Stimulus; Structure; System; Testing; Therapeutic; Tubulin; Variant; Virulence; Virulence Factors; X-Ray Crystallography; Yersinia enterocolitica; Yersinia pestis; design; experimental study; genetic regulatory protein; inhibitor/antagonist; kinetosome; mortality; new therapeutic target; novel; pathogen; periplasm; polymerization; prevent; public health relevance; response; scaffold

DESCRIPTION (provided by applicant): Antibiotic resistant and pathogenic Gram-negative bacteria are an increasingly important public health concern and are expected to soon surpass methicillin-resistant S. aureus as the principal cause of mortality due to bacterial infection. Despite evident need, new antibiotics are not being developed at an adequate rate and most effort involves modifications of existing drugs, rather than identification and development of novel drug targets. An attractive target for the much-needed development of new antibiotic therapeutics is the Type Three Secretion System (T3SS), a virulence factor delivery machine that is conserved among over 25 species of Gram-negative bacteria (including category A, B, and C pathogens). The T3SS is a multi-protein needle-like machine that spans the bacterial and host membranes and delivers protein translocator molecules into the membrane of the target cell and effector molecules into the cytosol of the target cell. The effectors promote virulence by co-opting cellular processes and subverting host defenses. While the molecular mechanisms of TTSS regulation are largely unknown, key requirements are that the pore is constitutively closed, that it opens in response to a stimulus, and secretion is an orderly, hierarchical process. Effectors are secreted directly into the host cell, through a preformed translocon pore. This pore is composed of secreted translocator proteins that must be secreted prior to effectors. A key regulatory protein is the "plug" which blocks the pore. Following plug protein secretion translocators are secreted, followed by effectors. In strains where plug proteins have been deleted, effectors are secreted constitutively, translocator secretion is severely defective, and the strains are non-virulent. The origin of the essential translocator-effector hierarchy is unknown. We have recently determined the first structure of a plug protein bound to a chaperone for a translocator. This structure reveals that plugs are molecular scaffolds that are tethered to translocators. We intend to further elucidate the role of plug-translocator scaffolding in multiple gram-negative species, and to understand the novel effector function of the Chlamydial plug protein. We have shown these proteins to possess novel tubulin binding function are poised, with our recent structure, to determine the molecular strategies that Chlamydia use to regulate the host's microtubule cytoskeleton. Finally, we will evaluate the chaperone-translocator interaction as a novel therapeutic target for the development of broad-spectrum antibiotics.

描述（由申请人提供）：抗生素耐药和致病性革兰氏阴性菌是日益重要的公共卫生问题，预计很快将超过耐甲氧西林金黄色葡萄球菌，成为细菌感染导致死亡的主要原因。尽管有明显的需求，但新抗生素的开发速度不够快，而且大多数努力涉及对现有药物的修改，而不是确定和开发新的药物靶点。第三型分泌系统（T3SS）是开发新型抗生素治疗急需的一个有吸引力的目标，它是一种毒力因子传递机器，在超过25种革兰氏阴性菌（包括a、B和C类病原体）中保守存在。T3SS是一种多蛋白针状机器，它跨越细菌和宿主膜，将蛋白质转运分子输送到靶细胞的膜中，将效应分子输送到靶细胞的细胞质中。效应物通过