Reciprocal regulation of persistence in the environment and pathogenesis of Acinetobacter baumannii

鲍曼不动杆菌环境持久性和发病机制的相互调节

• 批准号: 10054498
• 负责人: HARRY L. MOBLEY
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054498
• 关键词: Acinetobacter baumannii; Address; Anabolism; Anatomy; Animal Model; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Bacterial Physiology; Biochemistry; Biological Assay; Blood Circulation; Catabolism; Clinical; Collaborations; Complex; Dangerousness; Development; Disinfectants; Drug resistance; Environment; Escherichia coli; Foundations; Gene Expression; Genes; Genetic; Goals; Gram-Negative Bacteria; High Prevalence; Immunocompromised Host; Infection; Infection prevention; Knowledge; Laboratories; Liquid Chromatography; Mass Spectrum Analysis; Medical; Medical Device; Metabolic Pathway; Metabolism; Michigan; Microbial Biofilms; Molecular; Molecular Biology; Multi-Drug Resistance; Nosocomial Infections; Pathogenesis; Pathogenicity; Pathway interactions; Performance; Phenotype; Physiology; Play; Postoperative Care; Production; Proteins; Proteomics; Pseudomonas aeruginosa; Public Health; Regulation; Resistance; Respiratory System; Role; Sepsis; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Surface; Testing; Therapeutic Agents; Universities; Urinary tract; Urinary tract infection; Vibrio cholerae; Virulence; Water; Work; World Health Organization; antimicrobial; bacterial genetics; environmental stressor; fitness; gene induction; genetic approach; high throughput screening; in vivo; individual patient; interdisciplinary approach; mortality; mouse model; mutant; new therapeutic target; novel; novel therapeutics; pathogen; pathogenic bacteria; prevent; prophylactic; tandem mass spectrometry; transcriptome sequencing; transposon sequencing; ventilator-associated pneumonia; wound

Project Summary/Abstract Acinetobacter baumannii (AB) is a nosocomial, multi-drug resistant pathogenic gram-negative bacterium. It is a serious threat among immunocompromised individuals and for patients in intensive and post-operative care units. AB can infect a wide range of anatomic sites including the respiratory tract, bloodstream, wounds and the urinary tract. Its long-term persistence on abiotic surfaces, such as medical devices, and resistance to disinfectants and antibiotics exacerbate the potential of this bacterium as a dangerous pathogen. Moreover, the high prevalence of infection and associated multi-drug resistance, leaves few, if any, antimicrobial treatment options. Accordingly, the World Health Organization (WHO) lists AB as the number one priority among the bacterial pathogens for which new antimicrobials are urgently needed. However, despite its clinical importance, relatively little is known about the molecular basis of AB persistence in the environment, or its mechanisms of pathogenesis. To address these questions, we have identified, by an in vivo transposon-sequencing screen, the full set of genes required by AB during bloodstream infection. Genes predicted to be involved in the metabolism (biosynthesis and catabolism) of the signaling molecule c-di-GMP (cdG), a master regulator of biofilm formation, were among the genes identified. By using a genetic approach in both Escherichia coli and AB, we identified two functional genes; one involved in the biosynthesis, and one in the catabolism. The overall objective of this application is to determine the contribution of the cdG in both persistence in the environment and pathogenesis of AB. Our central hypothesis is the cdG plays a critical role in the infectious cycle of AB by coordinating its transition between the environment and the host, and vice-versa. To test this central hypothesis, we are proposing the following aims: 1) Assess the role of the cdG in persistence and resistance to environmental stresses and colonization of the bloodstream; and 2) Characterize the regulatory networks controlled by cdG. Taken together, this project will lay the foundations in our much-needed understanding on the mechanisms by which AB persists in the environment and infects its host. Furthermore, this work has the potential to identify novel drug targets to both treat AB infections and prevent its persistence on abiotic surfaces. Finally, this knowledge could also be broadly applicable and be used to treat other pathogens that employ a similar infection cycle to AB.

项目摘要/摘要 鲍曼尼杆菌（AB）是一种医院，耐多药的致病革兰氏阴性细菌。是一个 免疫功能低下的个体和对术后和术后护理中的患者的严重威胁 单位。 AB会感染各种解剖部位，包括呼吸道，血液，伤口和 尿路。它长期对非生物表面（例如医疗设备）的持久性以及对 消毒剂和抗生素加剧了该细菌作为危险病原体的潜力。而且， 感染和相关的多药抗性的高流行率很少（如果有）抗菌治疗 选项。因此，世界卫生组织（WHO）将AB列为 迫切需要新抗菌剂的细菌病原体。但是，尽管具有临床重要性，但 关于环境中AB持久性的分子基础，相对较少，其机制 发病。为了解决这些问题，我们已经通过体内转座子屏幕屏幕确定了 AB在血液感染期间需要全套基因。预计将参与新陈代谢的基因 信号分子C-DI-GMP（CDG）的（生物合成和分解代谢），生物膜形成的主要调节剂， 是确定的基因之一。通过在大肠杆菌和AB中使用遗传学方法，我们确定了两个 功能基因；一种参与生物合成，一种参与分解代谢。总体目标 应用是确定CDG在环境中的持久性和发病机理中的贡献 AB。我们的中心假设是CDG通过协调AB的感染周期起着至关重要的作用 环境与主机之间的过渡，反之亦然。为了检验这一中心假设，我们是 提出以下目的：1）评估CDG在持久性和抵抗环境中的作用 血液的压力和定殖； 2）表征由CDG控制的调节网络。 综上 AB坚持在环境中并感染其宿主。此外，这项工作有可能确定 新的药物靶标可以治疗AB感染并防止其对非生物表面的持续性。最后，这个 知识也可以广泛适用，并用于治疗采用类似感染的其他病原体 循环到AB。