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: 10171557
• 负责人: HARRY L. MOBLEY
• 金额: $ 23.4万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171557
• 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 鲍曼不动杆菌是医院内一种多重耐药的革兰氏阴性致病菌。这是一个 对免疫功能低下的个人以及重症监护和术后护理的患者构成严重威胁 单位。AB可感染广泛的解剖部位，包括呼吸道、血液、伤口和 尿路。它在非生物表面，如医疗器械上长期存在，并对 消毒剂和抗生素加剧了这种细菌作为危险病原体的潜力。此外， 感染的高流行率和相关的多重耐药，使得几乎没有抗菌药治疗 选择。因此，世界卫生组织(WHO)将AB列为 迫切需要新的抗菌剂的细菌病原体。然而，尽管它在临床上很重要， 关于AB在环境中持续存在的分子基础或其在环境中的作用机制，人们知之甚少 发病机制。为了解决这些问题，我们通过体内转座子测序筛选确定了 血液感染时AB所需的全套基因。被预测参与新陈代谢的基因 (生物合成和分解代谢)信号分子c-di-GMP(CDG)，生物膜形成的主要调节因子， 都在已确定的基因之列。通过在大肠杆菌和AB中使用遗传方法，我们鉴定了两个 功能基因；一个参与生物合成，一个参与分解代谢。这样做的总体目标是 应用是确定CDG在环境中的持久性和发病机制中的作用 AB的。我们的中心假设是CDG在AB的感染循环中发挥关键作用，它通过协调其 环境和宿主之间的转换，反之亦然。为了验证这一中心假设，我们正在 提出以下目标：1)评估CDG在环境持久性和抵抗力方面的作用 血流的应激和定植；2)CDG控制的调节网络的特征。 综上所述，该项目将为我们对这些机制的迫切需要的理解奠定基础。 这种AB在环境中持续存在，并感染其宿主。此外，这项工作有可能识别出 新的药物靶点，既可治疗AB感染，又可防止其在非生物表面持续存在。最后，这一点 知识也可以广泛适用，并可用于治疗其他使用类似感染的病原体。 骑自行车到AB。