A Novel Mechanism Regulating Virulence in Acinetobacter baumannii

鲍曼不动杆菌毒力调节新机制

• 批准号: 9898299
• 负责人: Philip N. Rather
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898299
• 关键词: Acinetobacter; Acinetobacter baumannii; Address; Afghanistan; Americas; Antibiotic Resistance; Antibiotics; Bacteria; Biochemical; Cell Density; Cell Differentiation process; Cells; Communicable Diseases; Data; Development; ESKAPE pathogens; Epigenetic Process; Exhibits; Feedback; Frequencies; Generations; Genes; Genetic Transcription; Goals; Heritability; Hospitals; Host Defense; Immune; Infection; Iraq; Lead; Lighting; Lung; Microbial Biofilms; Military Hospitals; Military Personnel; Modeling; Molecular; Molecular Conformation; Mus; Mutagenesis; Pathway interactions; Peptide Signal Sequences; Peptides; Phase; Phenotype; Phosphotransferases; Population; Predisposition; Regulation; Regulatory Pathway; Role; Signal Transduction; Single Nucleotide Polymorphism; Societies; Soft Tissue Infections; System; Transcription Coactivator; Transgenic Mice; Variant; Virulence; Virulent; Work; base; cell motility; daughter cell; density; extracellular; genome sequencing; high throughput screening; in vivo; inhibitor/antagonist; injured; mouse model; novel; novel therapeutics; pathogen; pathogenic bacteria; quorum sensing; resistant strain; response; sensor; small molecule; transcriptome sequencing; whole genome

Acinetobacter baumannii is a nosocomial pathogen responsible for an increasing number of infections in VA, civilian and military hospitals. This proposal will address a novel mechanism that regulates virulence in A. baumannii. This mechanism involves a molecular switch that interconverts A. baumannii between virulent and avirulent states. Cells in the virulent state grow as opaque colonies when viewed by indirect oblique lighting. In contrast, the avirulent form produces translucent colonies that are rapidly killed in-vivo by host defenses. The central component of this regulation is a transcriptional regulator (ABUW_1645) that acts as a bistable switch to drive the differentiation from opaque to translucent states. In addition, a peptide-based quorum sensing system activates the expression of this regulator through a two-component system when cells approach high density. The completion of our work will result in a greater understanding of this novel regulatory pathway that controls virulence. This information along with the strains constructed in this proposal will pave the way for the development of high- throughput screens to identify small molecules that either drive cells from the opaque (virulent) to the translucent (avirulent) state, or block the ability of translucent cells to switch to opaque. Ultimately, these inhibitors may result in the development of novel therapies to disable virulence in this increasingly important bacterial pathogen.

鲍曼不动杆菌是一种医院病原体， 退伍军人事务部、民用和军用医院的感染人数。这项建议会 解决一个新的机制，调节毒力在A。鲍曼不动杆菌。这 一种分子开关将A.鲍曼不动杆菌 有毒和无毒状态。处于毒性状态的细胞生长为不透明的集落 当通过间接倾斜照明观察时。相反，无毒形式产生 半透明的菌落，在体内被宿主防御迅速杀死。中央 该调节的组分是转录调节因子（ABUW_1645），其作用是 作为驱动从不透明到半透明状态的区分的开关。 此外，基于肽的群体感应系统激活了 当细胞接近高水平时， 密度的我们工作的完成将使我们对此有更深的理解 控制毒力的新调控途径。这些信息沿着 本提案中构建的菌株将为高- 通量筛选，以确定小分子，这些小分子要么驱动细胞从 不透明（有毒）到半透明（无毒）状态，或阻止的能力， 半透明单元格切换为不透明。最终，这些抑制剂可能导致 开发新的治疗方法，以使这种日益重要的 细菌病原体