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内病原体，导致鲍曼不动杆菌不断增加 退伍军人管理局、民用和军队医院的感染人数。该提案将 解决了调节鲍曼不动杆菌毒力的新机制。这 机制涉及一种分子开关，可在鲍曼不动杆菌之间相互转换 有毒和无毒状态。处于毒力状态的细胞生长为不透明的集落 当通过间接倾斜照明观看时。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 该调节的组成部分是转录调节因子 (ABUW_1645)，其作用 作为双稳态开关来驱动从不透明状态到半透明状态的分化。 此外，基于肽的群体感应系统可激活 当细胞接近高浓度时，该调节器通过双组分系统 密度。完成我们的工作将使我们对此有更深入的了解 控制毒力的新调控途径。此信息连同 该提案中构建的菌株将为高水平的开发铺平道路 通过通量筛选来识别小分子，这些小分子可以驱动细胞从 不透明（有毒）到半透明（无毒）状态，或阻止 半透明单元切换为不透明。最终，这些抑制剂可能会导致 开发新疗法以消除毒力，这一点日益重要 细菌病原体。