High-Risk Clones of Pseudomonas aeruginosa

铜绿假单胞菌的高风险克隆

基本信息

批准号：
10408175
负责人：
ALAN R HAUSER
金额：
$ 19.58万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-20 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408175
关键词：
Address Affect Alleles Antibiotic Resistance Antibiotics Centers for Disease Control and Prevention (U.S.)Collection Country DNA Disease Outbreaks Environment Epidemic Epidemiology Gastrointestinal tract structure Genotype Geographic Locations Hospitals Infection Infection Control Practitioners Institution Intervention Knowledge Link Medical Methods Mobile Genetic Elements Modernization Molecular Multi-Drug Resistance Mutation Nosocomial Infections Outcome Patients Phenotype Population Property Pseudomonas aeruginosa Pseudomonas aeruginosa infection Reporting Structure Testing Therapeutic Intervention antibiotic resistant infections burden of illness experimental study genome sequencing genomic locus gut colonization high risk high risk population insight mouse model multidrug-resistant Pseudomonas aeruginosa novel therapeutics pathogenic bacteria prevent priority pathogen resistance allele resistance gene targeted treatment whole genome

项目摘要

Project Summary Outbreaks of multidrug-resistant (MDR) Pseudomonas aeruginosa infections within medical institutions have been commonly reported for many years. We now know that most of these outbreaks are caused by a small group of widely dispersed MDR P. aeruginosa lineages, which are have been referred to as “high-risk clones” (HRCs). HRCs are highly antibiotic resistant PA lineages that have spread across countries and even continents to cause large numbers of infections. They emerged in the 1980s and 1990s and then rapidly disseminated. The best characterized HRCs are the multilocus sequence types (MLSTs) ST235, ST175, and ST111. HRCs are problematic for two reasons: (1) Because they readily spread within and between hospitals, they cause a disproportionate number of infections. (2) They are highly resistant to antibiotics. In fact, it appears that most MDR PA strains worldwide belong to these few HRC lineages. As expected, HRCs have also been linked to particularly poor outcomes. What has allowed HRCs to spread so widely and to become so resistant to antibiotics while the vast majority of P. aeruginosa STs are cultured only once and are antibiotic susceptible? Relatively few experiments have been performed to address this important question, but speculation has focused on two possibilities: (1) HRCs more effectively colonize the gastrointestinal (GI) tract than other P. aeruginosa strains. The GI tracts of patients are a major reservoir for P. aeruginosa in the hospital setting, and strains of P. aeruginosa capable of more effectively colonizing this niche would have a considerable advantage in persisting and spreading to new patients within and between institutions. (2) HRCs have properties that allow them to more efficiently acquire antibiotic resistance genes and alleles than conventional P. aeruginosa strains. Populations of HRCs harbor an impressive array of mobile genetic elements and chromosomal alleles that encode antibiotic resistance, suggesting that they are more amendable to acquiring exogenous DNA and evolving mutations than conventional strains. We hypothesize that HRCs are better able to colonize the GI tract and better able to acquire antibiotic-resistance determinants than conventional P. aeruginosa strains. To test these hypotheses, we will perform the following Specific Aims: (1) Use a mouse model to determine whether HRCs colonize the GI tract better than conventional P. aeruginosa strains. (2) Determine whether HRCs have properties that allow them to more readily become resistant to antibiotics. (3) Identify genetic loci that distinguish HRCs from conventional strains. Completion of these aims will provide insights into the mechanisms by which HRCs persist in the hospital environment and acquire MDR phenotypes. These insights in turn will highlight vulnerabilities that can be targeted by therapeutic interventions that prevent the spread and limit the antibiotic resistance of HRCs. Such interventions would impact not only some of the most common P. aeruginosa infections but also those that are the most difficult to treat.

项目概要医疗机构内多重耐药（MDR）铜绿假单胞菌感染暴发我们现在知道，大多数疫情都是由以下原因引起的。一小群广泛分布的耐多药铜绿假单胞菌谱系，被称为“高风险” 克隆”（HRC）是高度抗生素耐药的 PA 谱系，已遍布各个国家甚至各个国家。它们在 20 世纪 80 年代和 90 年代出现，然后迅速蔓延。传播性最好的 HRC 是多位点序列类型 (MLST) ST235、ST175 和 ST111.HRC 存在问题的原因有两个：(1) 因为它们很容易在医院内部和医院之间传播， (2) 事实上，它们对抗生素具有很强的耐药性。看来全世界大多数 MDR PA 菌株都属于这几个 HRC 谱系，正如预期的那样，HRC 具有。是什么导致人权委员会如此广泛地传播并变得如此之大。对抗生素有抗药性，而绝大多数铜绿假单胞菌 ST 仅培养一次并且是抗生素敏感性？已经进行了相对较少的实验来解决这个重要问题，但是推测集中在两种可能性上：(1) HRC 更有效地定植于胃肠道 (GI) 与其他铜绿假单胞菌菌株相比，患者的胃肠道是铜绿假单胞菌的主要储存库。医院环境中，能够更有效地定植该生态位的铜绿假单胞菌菌株将具有 (2) HRC 具有使它们比抗生素抗性基因和等位基因更有效地获得的特性传统的铜绿假单胞菌菌株 HRC 群体拥有一系列令人印象深刻的可移动遗传。编码抗生素耐药性的元件和染色体等位基因，表明它们更容易修正比传统菌株获得外源 DNA 和进化突变。能够更好地在胃肠道定殖并更好地获得抗生素耐药性决定因素为了检验这些假设，我们将执行以下具体操作。目的：(1) 使用小鼠模型来确定 HRC 是否比传统的 P. (2) 确定 HRC 是否具有使它们更容易变成铜绿假单胞菌的特性。 (3) 识别 HRC 与传统菌株的区别基因位点。这些目标将深入了解 HRC 在医院环境中持续存在的机制，获得 MDR 表型反过来将突出可以通过治疗来靶向的脆弱性。防止 HRC 传播并限制抗生素耐药性的干预措施。不仅影响一些最常见的铜绿假单胞菌感染，还影响那些最难感染的铜绿假单胞菌感染。对待。