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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要鲍曼不动杆菌（AB）是一种医院内的多重耐药致病性革兰氏阴性细菌。它是一个对免疫功能低下的个体以及接受重症监护和术后护理的患者构成严重威胁单位。 AB 可以感染多种解剖部位，包括呼吸道、血液、伤口和泌尿道。它在非生物表面（例如医疗设备）上的长期持久性，以及对消毒剂和抗生素加剧了这种细菌作为危险病原体的可能性。此外，感染率高以及相关的多重耐药性，使得抗菌治疗几乎没有（如果有的话）选项。因此，世界卫生组织 (WHO) 将 AB 列为第一要务。迫切需要新的抗菌药物的细菌病原体。然而，尽管其临床重要性，关于AB在环境中持续存在的分子基础或其机制知之甚少发病。为了解决这些问题，我们通过体内转座子测序筛选确定了 AB 在血流感染过程中所需的全套基因。预测参与新陈代谢的基因信号分子 c-di-GMP (cdG)（生物膜形成的主要调节因子）（生物合成和分解代谢），是已识别的基因之一。通过在大肠杆菌和 AB 中使用遗传方法，我们鉴定了两种功能基因；一种参与生物合成，一种参与分解代谢。本次活动的总体目标应用是为了确定 cdG 在环境中的持久性和发病机制中的贡献 AB 的。我们的中心假设是 cdG 通过协调 AB 的感染周期，在 AB 的感染周期中发挥着关键作用。环境和宿主之间的转换，反之亦然。为了检验这个中心假设，我们提出以下目标： 1) 评估 cdG 在持久性和抵抗环境影响方面的作用压力和血液定植； 2) 描述 cdG 控制的监管网络的特征。总而言之，该项目将为我们对机制的急需理解奠定基础 AB 会持续存在于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既可以治疗 AB 感染，又可以防止其在非生物表面上持续存在。最后，这个知识也可以广泛适用并用于治疗具有类似感染的其他病原体循环至AB。